Heteroarylsulfonyl-substituted pyridines and their use in the treatment of cancer

ABSTRACT

There is provided compounds of formula I (I) or pharmaceutically-acceptable salts thereof, wherein L, R 1 , R 2 , R 3  and X have meanings provided in the description, which compounds are useful in the treatment of cancers.

This application is a 371 of International ApplicationPCT/GB2018/050343, filed Feb. 7, 2018, which claims the benefit of U.S.Provisional Application No. 62/594,799, filed on Dec. 5, 2017, and toU.S. Provisional Application No. 62/455,639, filed on Feb. 7, 2017. Theentire contents of these applications are incorporated herein byreference in their entirety.

FIELD OF THE INVENTION

The present invention relates to novel compounds and compositions, andtheir use in the treatment of cancer. In particular, the inventionrelates to novel compounds, compositions and methods for the treatmentof cancers through specific and potent inhibition of thioredoxinreductase with minimal inhibition of glutathione reductase.

BACKGROUND OF THE INVENTION

The listing or discussion of an apparently prior-published document inthis specification should not necessarily be taken as an acknowledgementthat the document is part of the state of the art or is common generalknowledge.

Although the increased understanding of the role of oncogenes, and thedevelopment of new anticancer treatments and diagnosis, have improvedthe life expectancy of cancer patients, there is still a high medicalneed to find more effective and less toxic treatments for cancers, suchas breast cancer, head and neck cancer, glioblastoma, melanoma,leukaemia, and colon and lung cancer.

It is well known that excessive production of reactive oxygen species isa common feature of cancer cells due to their distorted metabolism andexaggerated replicative drive. Cancer cells are able to survive theirunnaturally high production of reactive oxygen species throughconcomitant upregulation of robust antioxidant defence mechanisms.

Radiotherapy and chemotherapy protocols compete against antioxidantdefence mechanisms, further increasing reactive oxygen species levelsbeyond adapted thresholds through targeting of multiple cellularcompartments and targets. Thus, sensitization of cancer cells to theirendogenous reactive oxygen species production can additionally inducecancer cell death. In contrast, normal cells have reserved capacity tocombat oxidative stress. With this in mind, it has been suggested thatif reactive oxygen species levels could be further increased, or thecellular defences against reactive oxygen species could be deliberatelyimpaired, these systems may serve to allow for a possible therapeuticmechanism of action for anticancer therapy (Luo, J., et al., Cell, 136,823 (2009); Trachootham, D., et al., Nat Rev Drug Discov, 8, 579(2009)).

Increased tolerance to oxidative stress of cancer cells can occurthrough activation of the two major antioxidant systems in human andother mammals: the glutathione and thioredoxin systems. Concomitantinhibition of the glutathione and thioredoxin systems therefore has beenproposed as a mechanism for anticancer activity (Harris, I. S., et al.,Cancer Cell 27, 211 (2015); Mandal, P. K., et al., Cancer Res, 70,9505-9514 (2010); Fath, M. A., et al., Clin Cancer Res., 17, 6206(2011)).

Cytosolic thioredoxin reductase is a key enzyme for the whole cytosolicthioredoxin system, which in turn is responsible for a cascade ofsignalling events and antioxidant activities (Arnér, E. S. J., BiochimBiophys Acta, 1790, 495-526 (2009)). A high expression level ofcytosolic thioredoxin reductase in various cancers correlates to a moresevere cancer phenotype, chemotherapeutic drug resistance, and poorprognosis.

However, as normal, non-cancerous cells require either the glutathioneor the thioredoxin systems for survival (Arnér, E. S. & Holmgren, A.,Eur J Biochem, 267, 6102 (2000); Lillig, C. H., Berndt, C. & Holmgren,A., Biochim Biophys Acta, 1780, 1304 (2008); Prigge, J. R., et al., FreeRadic Biol Med, 52, 803 (2012)), it is difficult to therapeuticallytarget both of these antioxidant systems without triggering majorunwanted toxicities.

It has been suggested that several chemotherapeutic protocols foranticancer treatment involve inhibition of cytosolic thioredoxinreductase together with other components of the cell (Becker, K. et al.Eur. J. Biochem., 267, 6118 (2000)). For example, motexafin gadolinium,marketed as a radiosensitizing drug and thioredoxin reductase inhibitor,is also a potent ribonucleotide reductase inhibitor (Hashemy, S. I., etal., J Biol Chem, 281, 10691 (2006)). Auranofin, a potent thioredoxinreductase inhibitor, concomitantly localizes to and damages themitochondria (Cox, A. G., et al, M. B., Biochem Pharmacol, 76, 1097-1109(2008); Krishnamurthy, D., et al., J Med Chem, 51, 4790 (2008);Rigobello, M. P., et al., Free Radic Res, 39, 687 (2005)).

The structure and function of thioredoxin reductase, biological effectsassociated with its inhibition, such as in its potential as a mechanismfor cancer treatment, and compounds previously disclosed as potentialinhibitors are reviewed in Zhang, B. et al., Expert Opinion onTherapeutic Patents (2016).

The present innovation relates to the development and usage of novelcompounds specifically and potently targeting cytosolic thioredoxinreductase, without targeting the closely related flavoproteinglutathione reductase that supports the function of the glutathionesystem, as a means of obtaining a new efficient anticancer treatmentthat at the same time presents limited toxic side effects.

In particular, the inventors have unexpectedly found that novel,pyridinyl sulfone compounds may achieve highly selective inhibition ofcytosolic thioredoxin reductase by acting as strongly-binding (and, insome cases, effectively irreversible) inhibitors of the enzyme withoutcausing significant inhibition of glutathione reductase.

Specifically, by potently inhibiting thioredoxin reductase selectivelyover glutathione reductase, the novel pyridinyl sulfones have thepotential to be effective against cancer forms having dysfunctionalredox status, with minimal general toxic effects to normal cells. Suchinhibitors may also be a suitable adjuvant therapy to be used inconjunction with radiotherapies or other chemotherapeutic approaches.Based on these surprising results, the present invention aims to providenew treatments for cancers.

Certain heteroarylsulfonyl-nitropyridines have been synthesized oralleged to be commercially available but with no use ascribed to them,as described in: Takahashi, T., et al, Chem Pharm Bull, 6, 369 (1958)and Talik, Z., et al, Prace Naukowe Akademii Ekonomicznej imienia OskaraLangego we Wroclawiu 255, 137 (1984).

International patent application WO 2010/138820 refers to thepreparation of various N,N′-diarylureas and N,N′-diarylthioureas thatare suggested to act to inhibit translation initiation and which arestated to be useful in the treatment of, for example, proliferativedisorders. This publication also lists a number of compounds identifiedin a chemical library.

International patent application WO 03/051366 describes certainpyridines as kinase inhibitors and their use in treating cancer.However, none the of exemplified pyridines carry nitro substituents andnone are linked via a sulfonyl moiety to an optionally substitutedheteroaryl group.

International patent application WO 2005/007621 describes certaincompounds as ubiquitin ligase inhibitors and their use in treating cellproliferative diseases. However, none of exemplified compounds contain anitro substituted pyridine that is linked via a sulfonyl moiety to anoptionally substituted heteroaryl group.

International patent application WO 99/36391 describes twobenzenesulfonamides as therapeutic agents. Neither contains a pyridinering having a nitro substituent.

International patent application WO 2005/121121 describes certaincompounds as glucose metabolism modulators useful for the treatment of,for example, diabetes and obesity. However, none of the exemplifiedcompounds contain a nitro substituted pyridine linked via a sulfonylmoiety to an optionally substituted heteroaryl group.

International patent application WO 2007/124546 describes3-cyano-4,6-diarylsubstituted pyridines useful for the treatment ofviral infections. However, none of the exemplified compounds contain anitro substituted pyridine linked via a sulfonyl moiety to an optionallysubstituted heteroaryl group.

International patent application WO 95/29897 describes certain(H⁺/K⁺)ATPase inhibitors and their use in treating viral infections.However, none of the exemplified compounds contain a nitro substitutedpyridine linked via a sulfonyl moiety to an optionally substitutedheteroaryl group.

International patent application WO 98/54139 describes a process for thepreparation of pyridines linked to, for example, an unsubstituted phenylvia a sulfonyl group. However, none of the exemplified compounds containa nitro substituted pyridine linked via a sulfonyl moiety to anoptionally substituted heteroaryl group.

International patent applications WO 2013/119931, WO 99/010320, WO99/18096 and WO 99/017777 describe certain compounds and their use intreating conditions such as cancer. However, none of the exemplifiedcompounds contain a nitro substituted pyridine linked via a sulfonylmoiety to an optionally substituted heteroaryl group.

International patent application WO 01/064642 describes certaincompounds and their use in treating coagulation disorders. However, noneof the exemplified compounds contain a nitro substituted pyridine linkedvia a sulfonyl moiety to an optionally substituted heteroaryl group.

International patent application WO 2011/022440 describes certaincompounds and their use for treating proliferative disorders. However,none of the exemplified compounds contain a nitro substituted pyridinelinked via a sulfonyl moiety to an optionally substituted heteroarylgroup.

Chinese patent application CN 102206172 describes certain antiviralcompounds. However, none of the exemplified compounds contain a nitrosubstituted pyridine linked via a sulfonyl moiety to an optionallysubstituted heteroaryl group.

DETAILED DESCRIPTION OF THE INVENTION

It has now been found that certain nitro substituted pyridines linkedvia a sulfonyl moiety to an optionally substituted heteroaryl group havesurprising properties which render such compounds useful in thetreatment of cancers.

Compounds of the Invention

In a first aspect of the invention, there is provided a compound offormula I

or a pharmaceutically acceptable salt thereof, wherein:

L represents —S(O)_(n)—;

n represents 2 or 1;

X represents a heteroaryl group, attached to L via a carbon atom,optionally substituted by one or more groups independently selected fromY;

R¹, R² and R³ each independently represent H, halo, R^(a1), —CN,-A^(a1)-C(Q^(a1))R^(b1), -A^(b1)-C(Q^(b1))N(R^(c1))R^(d1),—Ac^(c1)—C(Q^(c1))OR^(e1), -A^(d1)-S(O)_(p)R^(f1),-A^(e1)-S(O)_(p)N(R^(g1))R^(h1), -A^(f1)-S(O)_(p)OR^(i1), —N₃,—N(R^(j1))R^(k1), —N(H)CN, —NO₂, —ONO₂, —OR^(l1) or —SR^(m1);

each A^(a1) to A^(f1) independently represents a single bond,—N(R^(p1))— or —O—;

each Q^(a1) to Q^(c1) independently represents ═O, ═S, ═NR^(n1) or═N(OR^(o1));

each R^(a1) and R^(f1) independently represents C₁₋₆ alkyl, C₂₋₆ alkenylor C₂₋₆ alkynyl each optionally substituted by one or more groupsindependently selected from G^(1a), heterocyclyl optionally substitutedby one or more groups independently selected from G^(1b), aryloptionally substituted by one or more groups independently selected fromG^(1c), or heteroaryl optionally substituted by one or more groupsindependently selected from G^(1d);

each R^(b1), R^(c1), R^(d1), R^(e1), R^(g1), R^(h1), R^(i1), R^(j1),R^(k1), R^(l1), R^(m1), R^(n1), R^(o1) and R^(p1) independentlyrepresents H, C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl each optionallysubstituted by one or more groups independently selected from G^(1a),heterocyclyl optionally substituted by one or more groups independentlyselected from G^(1b), aryl optionally substituted by one or more groupsindependently selected from G^(1c), or heteroaryl optionally substitutedby one or more groups independently selected from G^(1d);

any of R^(c1) and R^(d1), R^(g1) and R^(h1) and/or R^(j1) and R^(k1) arelinked together to form, together with the nitrogen atom to which theyare attached, a 3- to 6-membered ring, which ring optionally containsone further heteroatom and which ring optionally is substituted by oneor more groups independently selected from halo, and C₁₋₃ alkyl, C₂₋₃alkenyl or C₂₋₃ alkynyl each optionally substituted by one or more halo,and ═O;

each G^(1a) and G^(1b) independently represents halo, —CN,—N(R^(a2))R^(b2), —OR^(c2), —SR^(d2) or ═O;

each G^(1c) and G^(1d) independently represents halo, —CN,—N(R^(a2))R^(b2), —OR^(c2) or —SR^(d2);

each R^(a2), R^(b2), R^(c2) and R^(d2) independently represents H orC₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl each optionally substituted byone or more fluoro; or

R^(a2) and R^(b2) are linked together to form, along with the nitrogenatom to which they are attached, a 3- to 6-membered ring, which ringoptionally contains one further heteroatom and which ring optionally issubstituted by one or more groups independently selected from fluoro,C₁₋₃ alkyl, C₂₋₃ alkenyl or C₂₋₃ alkynyl each optionally substituted byone or more fluoro;

each Y independently represents halo, R^(a3), —CN,-A^(a2)-C(Q^(a2))R^(b3), -A^(b2)C(Q^(b2))N(R^(c3))R^(d3),-A^(c2)-C(Q^(c2))OR^(e3), -A^(d2)-S(O)_(q)R^(f3),-A^(e2)-S(O)_(q)N(R^(g3))R^(h3), -A^(f2)-S(O)_(q)OR^(i3), —N₃,—N(R^(j3))R^(k3), —N(H)CN, —NO₂, —ONO₂, —OR^(l3) or —SR^(m3);

each Q^(a2) to Q^(c2) independently represents ═O, ═S, ═NR^(n3) or═N(OR^(o3));

each A^(a2) to A^(f2) independently represents a single bond,—N(R^(p3))— or —O—;

each R^(a3) and R^(f3) independently represents C₁₋₆ alkyl, C₂₋₆ alkenylor C₂₋₆ alkynyl each optionally substituted by one or more groupsindependently selected from G^(2a), heterocyclyl optionally substitutedby one or more groups independently selected from G^(2b), aryloptionally substituted by one or more groups independently selected fromG^(2c), or heteroaryl optionally substituted by one or more groupsindependently selected from G^(2d);

each R^(b3), R^(c3), R^(d3), R^(e3), R^(g3), R^(h3), R^(i3), R^(j3),R^(k3), R^(l3), R^(m3), R^(n3), R^(o3) and R^(p3) independentlyrepresents H, C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl each optionallysubstituted by one or more groups independently selected from G^(2a),heterocyclyl optionally substituted by one or more groups independentlyselected from G^(2b), aryl optionally substituted by one or more groupsindependently selected from G^(2c), or heteroaryl optionally substitutedby one or more groups independently selected from G^(2d); or

any two R^(c3) and R^(d3), R^(g3) and R^(h3) and/or R^(j3) and R^(k3)are linked together to form, along with the nitrogen atom to which theyare attached, a 3- to 6-membered ring, which ring optionally containsone further heteroatom and which ring optionally is substituted by oneor more groups independently selected from heterocyclyl optionallysubstituted by one or more groups independently selected from G^(2b),aryl optionally substituted by one or more groups independently selectedfrom G^(2c), or heteroaryl optionally substituted by one or more groupsindependently selected from G^(2d), and ═O;

each G^(2a) independently represents halo, —CN, —N(R^(j4))R^(k4),—OR^(l4), —SR^(m4) or ═O;

each G^(2b) independently represents halo, R^(a4), —CN,—N(R^(j4))R^(k4), —OR^(l4), —SR^(m4) or ═O;

each G^(2c) and G^(2d) independently represents halo, R^(a4), —CN,-A^(a3)-C(Q^(a4))R^(b4), -A^(b3)-C(Q^(b3))N(R^(c4))R^(d4),-A^(c3)-C(Q^(c3))OR^(e4), -A^(d3)-S(O)_(q)R^(f4),-A^(e3)-S(O)_(q)N(R^(g4))R^(h4), -A^(f3)-S(O)_(q)OR^(i4), —N₃,—N(R^(j4))R^(k4), —N(H)CN, —NO₂, —ONO₂, —OR^(l4) or —SR^(m4);

each Q^(a3) to Q^(c3) independently represents ═O, ═S, ═NR^(n4) or═N(OR^(o4));

each A^(a3) to A^(f3) independently represents a single bond,—N(R^(p4))— or —O—;

each R^(a4) and R^(f4) independently represents C₁₋₆ alkyl, C₂₋₆ alkenylor C₂₋₆ alkynyl each optionally substituted by one or more groupsindependently selected from G^(3a), heterocyclyl optionally substitutedby one or more groups independently selected from G^(3b), aryloptionally substituted by one or more groups independently selected fromG^(3c), or heteroaryl optionally substituted by one or more groupsindependently selected from G^(3d);

each R^(b4), R^(c4), R^(d4), R^(e4), R^(g4), R^(h4), R^(i4), R^(j4),R^(k4), R^(l4), R^(m4), R^(n4), R^(o4) and R^(p4) independentlyrepresents H, C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl each optionallysubstituted by one or more groups independently selected from G^(3a) orheterocyclyl optionally substituted by one or more groups independentlyselected from G^(3b), aryl optionally substituted by one or more groupsindependently selected from G^(3c), or heteroaryl optionally substitutedby one or more groups independently selected from G^(3d); or

any of R^(c4) and R^(d4), R^(g4) and R^(h4) and/or R^(j4) and R^(k4) arelinked together to form, together with the nitrogen atom to which theyare attached, a 3- to 6-membered ring, which ring optionally containsone further heteroatom and which ring optionally is substituted by oneor more groups independently selected G^(3b);

each G^(3a) and G^(3b) independently represents halo, R^(a5), —CN,—N(R^(b5))R^(c5), —OR^(d5), —SR^(e5) or ═O;

each R^(a5) independently represents C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆alkynyl each optionally substituted by one or more groups independentlyselected from G⁴;

each R^(b5), R^(c5), R^(d5) and R^(e5) independently represents H, orC₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl each optionally substituted byone or more groups independently selected from G⁴; or

each R^(b5) and R^(c5) are linked together to form, together with thenitrogen atom to which they are attached, a 3- to 6-membered ring, whichring optionally contains one further heteroatom and which ringoptionally is substituted by one or more groups independently selectedfrom G⁴;

each G⁴ independently represents halo, R^(a6), —CN, —N(R^(b6))R^(c6),—OR^(d6) or ═O;

each R^(a6) independently represents C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆alkynyl each optionally substituted by one or more fluoro;

each R^(b6), R^(c6) and R^(d6) independently represents H, or C₁₋₆alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl each optionally substituted by oneor more fluoro; and

each p and q independently represents 1 or 2,

which compounds and pharmaceutically acceptable salts thereof may bereferred to as compounds of the invention,

but with the provisos that the compound of formula I does not represent:

(A)

-   3-nitro-2-(pyridin-2-ylsulfonyl)pyridine,-   2-((3-nitropyridin-2-yl)sulfonyl)pyrimidine, or-   N-(6-chloro-2-((5-chloro-3-nitropyridin-2-yl)sulfonyl)pyridin-3-yl)acetamide;

or

(B)

-   3-nitro-2-[(3-nitro-2-thienyl)sulfinyl]-pyridine.

For the avoidance of doubt, compounds of formula I and pharmaceuticallyacceptable salts thereof, not including the provisos, may be referred toherein as compounds of the invention. Similarly, references to compoundsof the first aspect of the invention will refer to compounds of formulaI as defined in the first aspect of the invention, including theprovisos, and pharmaceutically acceptable salts thereof. As such,compounds of the first aspect of the invention represent a particularembodiment of compounds of the invention.

The skilled person will understand that references herein to compoundsof the invention (e.g. compounds of the first aspect of the invention)will include references to all embodiments and particular forms thereof.

Unless indicated otherwise, all technical and scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which this invention pertains.

Pharmaceutically-acceptable salts include acid addition salts and baseaddition salts. Such salts may be formed by conventional means, forexample by reaction of a free acid or a free base form of a compound ofthe invention with one or more equivalents of an appropriate acid orbase, optionally in a solvent, or in a medium in which the salt isinsoluble, followed by removal of said solvent, or said medium, usingstandard techniques (e.g. in vacuo, by freeze-drying or by filtration).Salts may also be prepared by exchanging a counter-ion of a compound ofthe invention in the form of a salt with another counter-ion, forexample using a suitable ion exchange resin.

Particular acid addition salts that may be mentioned include carboxylatesalts (e.g. formate, acetate, trifluoroacetate, propionate, isobutyrate,heptanoate, decanoate, caprate, caprylate, stearate, acrylate, caproate,propiolate, ascorbate, citrate, glucuronate, glutamate, glycolate,α-hydroxybutyrate, lactate, tartrate, phenylacetate, mandelate,phenylpropionate, phenylbutyrate, benzoate, chlorobenzoate,methylbenzoate, hydroxybenzoate, methoxybenzoate, dinitrobenzoate,o-acetoxybenzoate, salicylate, nicotinate, isonicotinate, cinnamate,oxalate, malonate, succinate, suberate, sebacate, fumarate, malate,maleate, hydroxymaleate, hippurate, phthalate or terephthalate salts),halide salts (e.g. chloride, bromide or iodide salts), sulfonate salts(e.g. benzenesulfonate, methyl-, bromo- or chloro-benzenesulfonate,xylenesulfonate, methanesulfonate, ethanesulfonate, propanesulfonate,hydroxyethanesulfonate, 1- or 2-naphthalene-sulfonate or1,5-naphthalenedisulfonate salts) or sulfate, pyrosulfate, bisulfate,sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate or nitrate salts, andthe like.

Particular base addition salts that may be mentioned include saltsformed with alkali metals (such as Na and K salts), alkaline earthmetals (such as Mg and Ca salts), organic bases (such as ethanolamine,diethanolamine, triethanolamine, tromethamine and lysine) and inorganicbases (such as ammonia and aluminium hydroxide). More particularly, baseaddition salts that may be mentioned include Mg, Ca and, mostparticularly, K and Na salts.

For the avoidance of doubt, compounds of the invention may exist assolids, and thus the scope of the invention includes all amorphous,crystalline and part crystalline forms thereof, and may also exist asoils. Where compounds of the invention exist in crystalline and partcrystalline forms, such forms may include solvates, which are includedin the scope of the invention. Compounds of the invention may also existin solution.

Compounds of the invention may contain double bonds and may thus existas E (entgegen) and Z (zusammen) geometric isomers about each individualdouble bond. All such isomers and mixtures thereof are included withinthe scope of the invention.

Compounds of the invention may also exhibit tautomerism. All tautomericforms and mixtures thereof are included within the scope of theinvention.

Compounds of the invention may also contain one or more asymmetriccarbon atoms and may therefore exhibit optical and/ordiastereoisomerism. Diastereoisomers may be separated using conventionaltechniques, e.g. chromatography or fractional crystallisation. Thevarious stereoisomers may be isolated by separation of a racemic orother mixture of the compounds using conventional, e.g. fractionalcrystallisation or HPLC, techniques. Alternatively the desired opticalisomers may be made by reaction of the appropriate optically activestarting materials under conditions which will not cause racemisation orepimerisation (i.e. a ‘chiral pool’ method), by reaction of theappropriate starting material with a ‘chiral auxiliary’ which cansubsequently be removed at a suitable stage, by derivatisation (i.e. aresolution, including a dynamic resolution); for example, with ahomochiral acid followed by separation of the diastereomeric derivativesby conventional means such as chromatography, or by reaction with anappropriate chiral reagent or chiral catalyst all under conditions knownto the skilled person. All stereoisomers and mixtures thereof areincluded within the scope of the invention.

As used herein, references to halo and/or halogen will independentlyrefer to fluoro, chloro, bromo and iodo (for example, fluoro andchloro).

Unless otherwise specified, C_(1-z) alkyl groups (where z is the upperlimit of the range) defined herein may be straight-chain or, when thereis a sufficient number (i.e. a minimum of two or three, as appropriate)of carbon atoms, be branched-chain, and/or cyclic (so forming a C_(3-z)cycloalkyl group). When there is a sufficient number (i.e. a minimum offour) of carbon atoms, such groups may also be part cyclic (so forming aC_(3-z) partial cycloalkyl group). Part cyclic alkyl groups that may bementioned include cyclopropylmethyl and cyclohexylethyl. When there is asufficient number of carbon atoms, such groups may also be multicyclic(e.g. bicyclic or tricyclic) or spirocyclic.

Unless otherwise specified, C_(2-z) alkenyl groups (where z is the upperlimit of the range) defined herein may be straight-chain or, when thereis a sufficient number (i.e. a minimum of three) of carbon atoms, bebranched-chain, and/or cyclic (so forming a C_(4-z) cycloalkenyl group).When there is a sufficient number (i.e. a minimum of five) of carbonatoms, such groups may also be part cyclic. Part cyclic alkenyl groupsthat may be mentioned include cyclopentenylmethyl andcyclohexenylmethyl. When there is a sufficient number of carbon atoms,such groups may also be multicyclic (e.g. bicyclic or tricyclic) orspirocyclic.

Unless otherwise specified, C_(2-z) alkynyl groups (where z is the upperlimit of the range) defined herein may be straight-chain or, when thereis a sufficient number (i.e. a minimum of four) of carbon atoms, bebranched-chain.

For the avoidance of doubt, the skilled person will understand that theterm alkyl will refer to saturated hydrocarbon moieties, whereas theterm alkenyl will refer to unsaturated hydrocarbon moieties containingat least one carbon-carbon double bond and the term alkynyl will referto unsaturated hydrocarbon moieties containing at least onecarbon-carbon triple bond, which alkyl, alkenyl and alkynyl groups maybe referred to collectively as hydrocarbyl groups. Further, suchunsaturated hydrocarbon moieties will be referred to by reference to thehighest degree of unsaturation comprised therein (e.g. a hydrocarbonmoiety comprising at least one carbon-carbon double bond and at leastone carbon-carbon triple bond will be referred to as alkynyl, althoughsuch moieties may also be referred to using terms such as “alkenylalkynyl” and the like).

As used herein, the term heterocyclyl may refer to non-aromaticmonocyclic and bicyclic heterocyclyl groups (which groups may further bebridged) in which at least one (e.g. one to four) of the atoms in thering system is other than carbon (i.e. a heteroatom), and in which thetotal number of atoms in the ring system is between three and twelve(e.g. between five and ten and, most preferably, between three andeight, e.g. a 5- or 6-membered heterocyclyl group). Further, suchheterocyclyl groups may be saturated, forming a heterocycloalkyl, orunsaturated containing one or more carbon-carbon or, where possible,carbon-heteroatom or heteroatom-heteroatom double and/or triple bonds,forming for example a C_(2-z) (e.g. C_(4-z)) heterocycloalkenyl (where zis the upper limit of the range) or a C_(7-z) heterocycloalkynyl group.C_(2-z) heterocyclyl groups that may be mentioned include7-azabicyclo-[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl,6-azabicyclo[3.2.1]-octanyl, 8-azabicyclo[3.2.1]octanyl, aziridinyl,azetidinyl, 2,3-dihydroisothiazolyl, dihydropyranyl, dihydropyridinyl,dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including1,3-dioxolanyl), dioxanyl (including 1,3-dioxanyl and 1,4-dioxanyl),dithianyl (including 1,4-dithianyl), dithiolanyl (including1,3-dithiolanyl), imidazolidinyl, imidazolinyl, isothiazolidinyl,morpholinyl, 7-oxabicyclo[2.2.1]heptanyl, 6-oxabicyclo[3.2.1]-octanyl,oxetanyl, oxiranyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl,pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl,3-sulfolenyl, tetrahydropyranyl, tetrahydrofuryl, tetrahydropyridinyl(such as 1,2,3,4-tetrahydropyridinyl and 1,2,3,6-tetrahydropyridinyl),thietanyl, thiiranyl, thiolanyl, tetrahydrothiopyranyl, thiomorpholinyl,trithianyl (including 1,3,5-trithianyl), tropanyl and the like.Substituents on heterocyclyl groups may, where appropriate, be locatedon any atom in the ring system including a heteroatom. Further, in thecase where the substituent is another cyclic compound, then the cycliccompound may be attached through a single atom on the heterocyclylgroup, forming a so-called “spiro”-compound. The point of attachment ofheterocyclyl groups may be via any atom in the ring system including(where appropriate) a further heteroatom (such as a nitrogen atom), oran atom on any fused carbocyclic ring that may be present as part of thering system. Heterocyclyl groups may also be in the N- or S-oxidisedform.

At each occurrence when mentioned herein, particular heterocyclyl groupsthat may be mentioned include 3- to 8-membered heterocyclyl groups (e.g.a 4- to 6-membered heterocyclyl group).

As may be used herein, the term aryl includes references to C₆₋₁₄ (e.g.C₆₋₁₀) aromatic groups. Such groups may be monocyclic or bicyclic and,when bicyclic, be either wholly or partly aromatic. C₆₋₁₀ aryl groupsthat may be mentioned include phenyl, naphthyl,1,2,3,4-tetrahydronaphthyl, indanyl, and the like (e.g. phenyl, naphthyland the like, such as phenyl). For the avoidance of doubt, the point ofattachment of substituents on aryl groups may be via any carbon atom ofthe ring system.

As may be used herein, the term heteroaryl (or heteroaromatic) includesreferences to 5- to 14- (e.g. 5- to 10-, such as 5- or 6-) memberedheteroaromatic groups (as may be specified) containing one or moreheteroatoms selected from oxygen, nitrogen and/or sulfur. Wherepossible, such heteroaryl groups may comprise one, two, or three rings,of which at least one is aromatic. Substituents onheteroaryl/heteroaromatic groups may, where appropriate, be located onany atom in the ring system including a heteroatom. Unless otherwisespecified, the point of attachment of heteroaryl/heteroaromatic groupsmay be via any atom in the ring system including (where appropriate) aheteroatom. Bicyclic heteroaryl/heteroaromatic groups may comprise abenzene ring fused to one or more further aromatic or non-aromaticheterocyclic rings, in which instances, the point of attachment of thepolycyclic heteroaryl/heteroaromatic group may be via any ring includingthe benzene ring or the heteroaryl/heteroaromatic or heterocyclyl ring.Examples of heteroaryl/heteroaromatic groups that may be mentionedinclude pyridinyl, pyrrolyl, furanyl, thiophenyl, oxadiazolyl,thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl,isoxazolyl, isothiazolyl, imidazolyl, imidazopyrimidinyl,imidazothiazolyl, thienothiophenyl, pyrimidinyl, furopyridinyl, indolyl,azaindolyl, pyrazinyl, pyrazolopyrimidinyl, indazolyl, pyrimidinyl,quinolinyl, isoquinolinyl, quinazolinyl, benzofuranyl, benzothiophenyl,benzoimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl andpurinyl. The oxides of heteroaryl/heteroaromatic groups are alsoembraced within the scope of the invention (e.g. the N-oxide). As statedabove, heteroaryl includes polycyclic (e.g. bicyclic) groups in whichone ring is aromatic (and the other may or may not be aromatic). Hence,other heteroaryl groups that may be mentioned include e.g.benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, dihydrobenzo[d]isothiazole,3,4-dihydrobenz[1,4]oxazinyl, dihydrobenzothiophenyl, indolinyl, 5H,6H,7H-pyrrolo[1,2-b]pyrimidinyl, 1,2,3,4-tetrahydroquinolinyl,thiochromanyl and the like.

For the avoidance of doubt, as used herein, references to heteroatomswill take their normal meaning as understood by one skilled in the art.Particular heteroatoms that may be mentioned include phosphorus,selenium, tellurium, silicon, boron, oxygen, nitrogen and sulfur (e.g.oxygen, nitrogen and sulfur).

For the avoidance of doubt, references to polycyclic (e.g. bicyclic)groups (e.g. when employed in the context of heterocyclyl groups) willrefer to ring systems wherein more than two scissions would be requiredto convert such rings into a straight chain, with the minimum number ofsuch scissions corresponding to the number of rings defined (e.g. theterm bicyclic may indicate that a minimum of two scissions would berequired to convert the rings into a straight chain). For the avoidanceof doubt, the term bicyclic (e.g. when employed in the context ofheterocyclyl groups) may refer to groups in which the second ring of atwo-ring system is formed between two adjacent atoms of the first ring,and may also refer to groups in which two non-adjacent atoms are linkedby either an alkylene or heteroalkylene chain (as appropriate), whichlater groups may be referred to as bridged.

For the avoidance of doubt, when an aryl or an heteroaryl group issubstituted with a group via a double bond, such as ═O, it is understoodthat the aryl or heteroaryl group is partly aromatic, i.e. the aryl orheteroaryl group consists of at least two rings where at least one ringis not aromatic.

The present invention also embraces isotopically-labelled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature (or the most abundant one found in nature).

All isotopes of any particular atom or element as specified herein arecontemplated within the scope of the compounds of the invention. Hence,the compounds of the invention also include deuterated compounds, i.e.in which one or more hydrogen atoms are replaced by the hydrogen isotopedeuterium.

For the avoidance of doubt, in cases in which the identity of two ormore substituents in a compound of the invention may be the same, theactual identities of the respective substituents are not in any wayinterdependent. For example, in the situation in which two or more Ygroups are present, those Y groups may be the same or different.Similarly, where two or more Y groups are present and each representR^(a2), the R^(2a) groups in question may be the same or different.Likewise, when more than one R^(a1) is present and each independentlyrepresents C₁₋₆ alkyl substituted by one or more G^(1a) group, theidentities of each G^(1a) are in no way interdependent.

For the avoidance of doubt, when a term such as “A^(a1) to A^(f1)” isemployed herein, this will be understood by the skilled person to meanA^(a1), A^(b1), A^(c1), A^(d1), A^(e1) and A^(f1) inclusively. Unlessotherwise stated, the same reasoning will apply to other such terms usedherein.

The skilled person will appreciate that compounds of the invention thatare the subject of this invention include those that are stable. Thatis, compounds of the invention include those that are sufficientlyrobust to survive isolation, e.g. from a reaction mixture, to a usefuldegree of purity.

All embodiments of the invention and particular features mentionedherein may be taken in isolation or in combination with any otherembodiments and/or particular features mentioned herein (hencedescribing more particular embodiments and particular features asdisclosed herein) without departing from the disclosure of theinvention.

For the avoidance of doubt, the compounds listed in the provisosprovided in the first aspect of the invention (and therefore excluded ascompounds of formula I in the first aspect of the invention) may berepresented structurally as follows:

In particular embodiments of compounds of the invention (includingcompounds of the first aspect of the invention), the heteroaryl grouprepresenting X is a 5- to 6-membered heteroaryl group. Thus, in suchembodiments, X represents a 5- to 6-heteroaryl group, attached to L viaa carbon atom, optionally substituted by one or more groupsindependently selected from Y.

For the avoidance of doubt, the skilled person will understand that 5-to 6-membered heteroaryl groups will be necessarily monocyclic.

Particular compounds of the invention that may be mentioned includethose in which n represents 2.

Further compounds of the invention that may be mentioned include thosein which n represents 1.

Particular compounds of the invention that may be mentioned (e.g. inrelation to the first aspect of the invention) include those in which Xis unsubstituted or substituted with one or two Y groups.

For example, particular compounds of the invention that may be mentionedinclude those in which X is unsubstituted.

Further compounds of the invention that may be mentioned include thosein which X is substituted with one Y.

More particular compounds of the invention that may be mentioned includethose in which each Y independently represents halo (such as fluoro orchloro), R^(a3), —N(R^(j3))R^(k3) or —OR^(l3).

More particular compounds of the invention that may be mentioned includethose in which:

each R^(a3) independently represents C₁₋₆ alkyl (e.g. methyl) optionallysubstituted by one or more fluoro; and/or (e.g. and)

each R^(j3), R^(k3) and R^(l3) independently represents H, or C₁₋₆alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl) each optionallysubstituted by one or more fluoro.

More particular compounds of the invention that may be mentioned includethose in which:

X is unsubstituted or substituted with one Y;

each Y (i.e. where present) independently represents halo (such asfluoro or chloro), —N(R^(j3))R^(k3), —OR^(l3), or R^(a3);

each R^(a3) independently represents C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆alkynyl (e.g. C₁₋₆ alkyl, such as methyl) each optionally substituted byone or more fluoro; and/or (e.g. and)

each R^(j3), R^(k3) and R^(l3) independently represents H, or C₁₋₆alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl) each optionallysubstituted by one or more fluoro.

More particular compounds of the invention that may be mentioned includethose in which:

X is unsubstituted or substituted with one Y; and/or (e.g. and)

Y represents halo (e.g. fluoro or chloro) —OC₁₋₆ alkyl, —OC₂₋₆ alkenylor —OC₂₋₆ alkynyl (e.g. —OC₁₋₆ alkyl) each optionally substituted by oneor more fluoro (e.g. —OCH₃), or C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl(e.g. C₁₋₆ alkyl) each optionally substituted by one or more fluoro(e.g. —CH₃).

Yet more particular compounds of formula I that may be mentioned includethose in which:

X is unsubstituted or substituted with one Y; and/or (e.g. and)

Y represents fluoro, chloro, or C₁₋₆ alkyl optionally substituted by oneor more fluoro (e.g. —CH₃).

In certain embodiments of compounds of formula I, each Y (where present)represents methyl optionally substituted with one or more fluoro (e.g.—CH₃).

Thus, examples of more particular compounds that may be mentionedinclude those in which:

X is unsubstituted or substituted with one Y; and/or (e.g. and)

Y represents methyl optionally substituted with one or more fluoro (e.g.—CH₃).

In a particular embodiment (i.e. of compounds of the invention, e.g.compounds of the first aspect of the invention), the compound of formulaI is a compound of formula Ia

wherein:

L, R¹, R² and R³ and are defined for compounds of the invention(including all particular features and embodiments thereof);

each of Z¹ to Z⁵ represents CR⁴ to CR⁸, respectively, with the exceptionthat one or two of Z¹ to Z⁵ instead represents a heteroatom, which wherepossible may be substituted with R⁹, and optionally one of Z¹ to Z⁵ mayinstead represent a direct bond; and

each of R⁴ to R⁹ represents H or Y as defined herein for compounds ofthe invention (including all particular features and embodimentsthereof).

For the avoidance of doubt, where the compound of formula I (i.e. thecompound of the invention) is a compound of formula Ia, compounds of theinvention (e.g. compounds of the first aspect of the invention) includepharmaceutically acceptable salts of compounds of formula Ia.

For the avoidance of doubt, in compounds of formula Ia, the ringcontaining Z¹ to Z⁵ is aromatic (as indicated by the presence of thecircle inside that ring as depicted hereinabove).

For the avoidance of doubt, in relation to all compounds having such asgroup defined herein, the group X may be defined as a moiety ofstructural formula:

wherein the bond dissected by the dashed line is the bond forming theattachment to the required sulfonyl moiety, and wherein Z¹ to Z⁵ are asdefined herein for compounds of formula Ia (including all embodimentsand features thereof).

In a particular embodiment of compounds of formula Ia, where Z¹ to Z⁵represents a heteroatom, which where possible may be substituted withR⁹, that group may represent O, S, N or NR⁹.

In a particular embodiment of compounds of formula Ia, each of Z¹ to Z⁵represents CR⁴ to CR⁸, respectively, with the exception that one or twoof Z¹ and Z³ to Z⁵ instead represents a heteroatom, which where possiblemay be substituted with R⁹, and optionally Z³ may instead represent adirect bond.

In a particular embodiment of compounds of formula Ia, R⁹ (wherepresent) represents H.

Thus, in a particular embodiment of compounds of formula Ia, where Z¹ toZ⁵ represents a heteroatom, which where possible may be substituted withR⁹, that group may represent O, S, N or NH.

In a particular embodiment, each of R⁴ to R⁹ represents H with theexception that one or two (e.g. one) of R⁴ to R⁹ (e.g. one or two of R⁴to R⁸) may optionally instead represent Y as defined herein forcompounds of formula I (including all particular features andembodiments thereof).

In a more particular embodiment, each of R⁴, R⁵, R⁷, R⁸ and R⁹ (wherepresent) represents H and R⁶ (where present) represents H or Y asdefined for compounds of formula I (including all particular featuresand embodiments thereof).

In a yet more particular embodiment, each of R⁴, R⁵, R⁷, R⁸ and R⁹(where present) represents H and R⁶ (where present) represents H or Y,wherein Y represents halo (e.g. fluoro or chloro), C₁₋₆ alkyl, C₂₋₆alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl) each optionally substituted byone or more fluoro (e.g. —CH₃, —CHF₂ or —CF₃), or —OC₁₋₆ alkyl, —OC₂₋₆alkenyl or —OC₂₋₆ alkynyl (e.g. —OC₁₋₆ alkyl) optionally substituted byone or more fluoro (e.g. —OCH₃, —OCHF₂ or —OCF₃).

In a yet more particular embodiment, each of R⁴, R⁵, R⁷, R⁸ and R⁹(where present) represents H and R⁶ (where present) represents H or Y,wherein Y represents C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₆alkyl) each optionally substituted by one or more fluoro (e.g. —CH₃,—CHF₂ or —CF₃).

In a yet more particular embodiment, each of R⁴, R⁵, R⁷, R⁸ and R⁹(where present) represents H and R⁶ (where present) represents H or Y,wherein Y represents methyl optionally substituted by one or morefluoro.

For example, particular compounds of formula I that may be mentionedinclude those in which X represents pyridinyl (e.g. 2-pyridinyl or4-pyridinyl, such as 2-pyridinyl), pyrimidinyl (e.g. 2-pyrimidinyl or4-pyrimidinyl, such as 2-pyrimidinyl), imidazolyl (e.g. 2-imidazolyl)and thiazolyl (e.g. 2-thiazolyl), each optionally substituted with oneor more (e.g. one) Y group.

Thus, yet more particular compounds of formula I that may be mentionedinclude those in which X represents pyridinyl (e.g. 2-pyridinyl or4-pyridinyl, such as 2-pyridinyl), pyrimidinyl (e.g. 2-pyrimidinyl),imidazolyl (e.g. 2-imidazolyl) and methyl thiazolyl (e.g.4-methyl-2-thiazolyl).

For example, in particular embodiments, when X represents pyridinyloptionally substituted with one or more Y group, that pyridinyl is a2-pyridinyl, particularly unsubstituted 2-pyridinyl.

Particular compounds of the invention (e.g. compounds of the firstaspect of the invention, including formula I and Ia, and all particularfeatures and embodiments thereof) that may be mentioned include those inwhich R¹, R² and R³ each independently represents H, halo, R^(a1),—N(R^(j1))R^(k1) or —OR^(l1).

More particular compounds of the invention that may be mentioned includethose in which:

each R^(a1) and R^(f1) independently represents C₁₋₆ alkyl, C₂₋₆ alkenylor C₂₋₆ alkynyl each optionally substituted by one or more groupsindependently selected from G^(1a), or heterocyclyl optionallysubstituted by one or more groups independently selected from G^(1b);and

each R^(b1), R^(c1), R^(d1), R^(e1), R^(g1), R^(h1), R^(i1), R^(j1),R^(k1), R^(l1), R^(m1), R^(n1), R^(o1) and R^(p1) independentlyrepresents H, C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl each optionallysubstituted by one or more groups independently selected from G^(1a) orheterocyclyl optionally substituted by one or more groups independentlyselected from G^(1b); or

any of R^(c1) and R^(d1), R^(g1) and R^(h1) and/or R^(j1) and R^(k1) arelinked together to form, together with the nitrogen atom to which theyare attached, a 3- to 6-membered ring, which ring optionally containsone further heteroatom and which ring optionally is substituted by oneor more groups independently selected from halo, and C₁₋₃ alkyl, C₂₋₃alkenyl or C₂₋₃ alkynyl each optionally substituted by one or more halo,and ═O.

More particular compounds of the invention that may be mentioned includethose in which:

each R¹, R² and R³ each independently represent H, halo, R^(a1),—N(R^(j1))R^(k1), —OR^(l1) or —SR^(m1) (e.g. H, halo, R^(a1),—N(R^(j1))R^(k1) or —OR^(l1)); and/or (e.g. and)

each of R^(a1), R^(j1), R^(k1), R^(l1) and R^(m1) independentlyrepresents C₁₋₆ alkyl (e.g. methyl) optionally substituted by one ormore fluoro.

In certain embodiments that may be mentioned, only R^(c1) and R^(d1),and/or R^(g1) and R^(h1) may alternatively be linked together in themanner described herein.

In more particular embodiments that may be mentioned, G^(1a) groups(i.e. where present as a substituent on R^(1a), which in such instancesmay be alternatively referred to as G^(1ax) groups) may represent halo(e.g. fluoro).

In particular embodiments, R¹, R² and R³ each independently represent H,halo (e.g. fluoro or chloro, such as chloro), —N(R^(j1))R^(k1) or—OR^(l1).

For example, particular compounds of the invention (e.g. compounds ofthe first aspect of the invention, including formula I and Ia, and allparticular features and embodiments thereof) that may be mentionedinclude those in which:

each R¹, R² and R³ each independently represent H, halo,—N(R^(j1))R^(k1) or —OR^(l1); and

each R^(j1), R^(k1) and R^(l1) independently represents C₁₋₆ alkyl, C₂₋₆alkenyl or C₂₋₆ alkynyl (e.g. C₁₋₆ alkyl, such as C₁₋₃ alkyl) eachoptionally substituted by one or more fluoro.

More particular compounds of the invention (e.g. compounds of the firstaspect of the invention, including formula I and Ia, and all particularfeatures and embodiments thereof) that may be mentioned include those inwhich:

each R¹, R² and R³ each independently represent H, halo (e.g. fluoro orchloro, such as chloro), —N(R^(j1))R^(k1) or —OR^(l1); and

each R^(j1), R^(k1) and R^(l1) represents methyl optionally substitutedby one or more fluoro.

Particular compounds of the invention (e.g. compounds of the firstaspect of the invention, including formula I and Ia, and all particularfeatures and embodiments thereof) that may be mentioned include those inwhich R² and R³ each represent H or fluoro.

More particular compounds of the invention (e.g. compounds of the firstaspect of the invention, including formula I and Ia, and all particularfeatures and embodiments thereof) that may be mentioned include those inwhich R² and R³ each represent H.

Particular compounds of the invention (e.g. compounds of the firstaspect of the invention, including formula I and Ia, and all particularfeatures and embodiments thereof) that may be mentioned include those inwhich R¹ represents other than H.

Thus, in particular embodiments, compounds of the invention (e.g.compounds of the first aspect of the invention, including formula I andIa, and all particular features and embodiments thereof) that may bementioned include those in which:

R² and R³ each represent H; and

R¹ represents H or, particularly, halo (e.g. fluoro or chloro, such aschloro), —N(R^(j1))R^(k1) or —OR^(l1), more particularly wherein eachR^(j1), R^(k1) and R^(l1) represents C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆alkynyl (e.g. C₁₋₆ alkyl or, particularly, C₁₋₃ alkyl, such as methyl)each optionally substituted by one or more fluoro.

In more particular embodiments, compounds of the invention (e.g.compounds of the first aspect of the invention, including formula I andIa, and all particular features and embodiments thereof) that may bementioned include those in which:

R² and R³ each represent H;

R¹ represents halo (e.g. fluoro or chloro, such as chloro),—N(R^(j1))R^(k1) or —OR^(l1); and

each R^(j1), R^(k1) and R^(l1) represents methyl optionally substitutedby one or more fluoro.

In certain embodiments, compounds of the invention (e.g. compounds ofthe first aspect of the invention, including formula I and Ia, and allparticular features and embodiments thereof) that may be mentionedinclude those in which R¹ represents —OC₁₋₃ alkyl optionally substitutedwith one or more fluoro.

In further embodiments, compounds of the invention (e.g. compounds ofthe first aspect of the invention, including formula I and Ia, and allparticular features and embodiments thereof) that may be mentionedinclude those in which R¹ represents —OCH₃.

Thus, in particular embodiments, compounds of the invention (e.g.compounds of the first aspect of the invention, including formula I andIa, and all particular features and embodiments thereof) that may bementioned include those in which:

R² and R³ each represent H; and

R¹ represents —OCH₃.

As indicated herein above, particular features and embodiments asdescribed herein may be combined without departing from the teaching ofthe invention.

For example, in a particular embodiments of compounds of the invention(e.g. compounds of the first aspect of the invention, including formulaI and Ia, and all particular features and embodiments thereof):

X represents a 5- to 6-membered heteroaryl group, attached to L via acarbon atom, optionally substituted by one or more (particularly, one ortwo) groups independently selected from Y;

each Y independently represents halo (such as fluoro or chloro, e.g.chloro), R^(a3), —N(R^(j3))R^(k3) or —OR^(l3); and

each R¹, R² and R³ each independently represents H, halo, R^(a1),—N(R^(j1))R^(k1) or —OR^(l1).

In further such embodiments of compounds of the invention (e.g.compounds of the first aspect of the invention, including formula I andIa, and all particular features and embodiments thereof):

X represents a 5- to 6-membered heteroaryl group, attached to L via acarbon atom, optionally substituted by one Y group;

Y represents methyl optionally substituted with one or more fluoro (e.g.—CH₃);

R² and R³ each represent H;

R¹ represents H or, particularly, halo (e.g. fluoro or chloro, such aschloro), —N(R^(j1))R^(k1) or —OR^(l1); and

each R^(j1), R^(k1) and R^(l1) represents C₁₋₆ alkyl, C₂₋₆ alkenyl orC₂₋₆ alkynyl (e.g. C₁₋₃ alkyl, such as methyl) each optionallysubstituted by one or more fluoro.

For the avoidance of doubt, the skilled person will understand that eachG^(3c) and G^(3d) may be construed relative to G^(3a) and G^(3b) in thesame manner as the corresponding G^(2c) and G^(2d) groups are construedrelative to construed relative to G^(2a) and G^(2b), i.e. such that:

G^(3c) and G^(3d) independently representing halo, R^(a5), —CN,-A^(a4)-C(Q^(a4))R^(b5), -A^(b4)-C(Q^(b4))N(R^(c5))R^(d5),-A^(c4)C(Q^(c4))OR^(e5), -A^(d5)-S(O)_(q)R^(f5),-A^(e4)-S(O)_(q)N(R^(g5))R^(h5), -A^(f4)-S(O)_(q)OR^(i5), —N₃,—N(R^(j5))R^(k5), —N(H)CN, —NO₂, —ONO₂, —OR^(l5) or —SR^(m5),

each Q^(a4) to Q^(c4) independently represents ═O, ═S, ═NR^(n5) or═N(OR^(o5));

each A^(a4) to A^(f4) independently represents a single bond,—N(R^(p5))— or —O—;

with each R^(f5) to R^(p5) independently representing H, or C₁₋₆ alkyl,C₂₋₆ alkenyl or C₂₋₆ alkynyl each optionally substituted by one or moregroups independently selected from G⁴, or with each R^(g5) and R^(h5),and R^(j5) and R^(k5) being linked together to form, together with thenitrogen atom to which they are attached, a 3- to 6-membered ring, whichring optionally contains one further heteroatom and which ringoptionally is substituted by one or more groups independently selectedfrom G⁴.

Particular compounds of the invention (including compounds of formula Iand Ia, and all embodiments and particular forms thereof) that may bementioned include the compounds of the examples as provided herein, or apharmaceutically acceptable salt thereof.

Where an example compound is indicated to have been obtained in aparticular salt form, the skilled person will understand that particularcompounds of the invention that may be mentioned include the free baseor free acid (as appropriate) of that compound, and vice versa. Further,where an example compound is indicated to have been obtained in aparticular salt form, particular compounds of the invention that may bementioned include other (i.e. different) pharmaceutically acceptablesalts of that compound.

Thus, for the avoidance of doubt, particular compounds of the inventionthat may be mentioned include:

-   6-methoxy-3-nitro-2-(pyridin-2-ylsulfonyl)pyridine;-   6-chloro-3-nitro-2-(pyridin-2-ylsulfonyl)pyridine;-   6-dimethylamino-3-nitro-2-(pyridin-2-ylsulfonyl)pyridine;-   6-methoxy-3-nitro-2-(pyridin-4-ylsulfonyl)pyridine;-   2-((6-methoxy-3-nitropyridin-2-yl)sulfonyl)pyrimidine;-   2-((1H-imidazol-2-yl)sulfonyl)-6-methoxy-3-nitropyridine; and-   2-((6-methoxy-3-nitropyridin-2-yl)sulfonyl)-4-methylthiazole,    and pharmaceutically acceptable salts thereof.

Compositions and Medical Uses

As discussed hereinbefore, compounds of the invention, and thereforecompositions and kits comprising the same, are useful aspharmaceuticals.

According to a second aspect of the invention there is provided acompound of the invention, as hereinbefore defined (i.e. in the firstaspect of the invention, including all embodiments and particularfeatures therein, but without the provisos), for use as apharmaceutical. Further, there is provided a compound of the invention,as hereinbefore defined, for use in medicine.

In a particular embodiment of the second aspect of the invention, thecompound of the invention is a compound of the first aspect of theinvention (i.e. including the provisos).

As indicated herein, compounds of the invention may be of particular usein treating cancers.

Thus, in a third aspect of the invention, there is provided a compoundof the invention, as hereinbefore defined (i.e. in the first aspect ofthe invention, including all embodiments and particular featurestherein, but without the provisos), for use in the treatment of cancer.

In an alternative third aspect of the invention, there is provided theuse of a compound of the invention, as hereinbefore defined, in themanufacture of a medicament for the treatment of cancer.

In a further alternative third aspect of the invention, there isprovided a method of treating cancer comprising administering to apatient in need thereof a therapeutically effective amount of a compoundof the invention.

In a particular embodiment of the third aspect of the invention, thecompound of the invention is a compound of the first aspect of theinvention (i.e. including the provisos).

The skilled person will understand that references to the treatment of aparticular condition (or, similarly, to treating that condition) taketheir normal meanings in the field of medicine. In particular, the termsmay refer to achieving a reduction in the severity of one or moreclinical symptom associated with the condition. For example, in the caseof a cancer, the term may refer to achieving a reduction of the amountof cancerous cells present (e.g. in the case of a cancer forming a solidtumour, indicated by a reduction in tumour volume).

As used herein, references to patients will refer to a living subjectbeing treated, including mammalian (e.g. human) patients.

As used herein, the term effective amount will refer to an amount of acompound that confers a therapeutic effect on the treated patient. Theeffect may be objective (i.e. measurable by some test or marker) orsubjective (i.e. the subject gives an indication of and/or feels aneffect).

Although compounds of the invention may possess pharmacological activityas such, certain pharmaceutically-acceptable (e.g. “protected”)derivatives of compounds of the invention may exist or be prepared whichmay not possess such activity, but may be administered parenterally ororally and thereafter be metabolised in the body to form compounds ofthe invention. Such compounds (which may possess some pharmacologicalactivity, provided that such activity is appreciably lower than that ofthe active compounds to which they are metabolised) may therefore bedescribed as “prodrugs” of compounds of the invention.

As used herein, references to prodrugs will include compounds that forma compound of the invention, in an experimentally-detectable amount,within a predetermined time, following enteral or parenteraladministration (e.g. oral or parenteral administration). All prodrugs ofthe compounds of the invention are included within the scope of theinvention.

Furthermore, certain compounds of the invention may possess no orminimal pharmacological activity as such, but may be administeredparenterally or orally, and thereafter be metabolised in the body toform compounds of the invention that possess pharmacological activity assuch. Such compounds (which also includes compounds that may possesssome pharmacological activity, but that activity is appreciably lowerthan that of the active compounds of the invention to which they aremetabolised), may also be described as “prodrugs”.

Thus, the compounds of the invention are useful because they possesspharmacological activity, and/or are metabolised in the body followingoral or parenteral administration to form compounds that possesspharmacological activity.

Without wishing to be bound by theory, it is believed that compounds ofthe invention wherein n represents 1 may be metabolised in vivo to formcorresponding compounds of the invention wherein n represents 2.

As indicated herein, the compounds of the invention may be useful in thetreatment of cancer (i.e. particular cancers).

Particular cancers that may be mentioned include those selected from thegroup comprising:

soft tissue cancers, such as sarcoma (e.g. angiosarcoma, fibrosarcoma,rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma andteratoma;

lung cancers, such as bronchogenic carcinoma (e.g. squamous cell,undifferentiated small cell, undifferentiated large cell,adenocarcinoma), alveolar (or bronchiolar) carcinoma, bronchial adenoma,sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, includingnon-small cell lung cancer;

gastrointestinal cancers: such as esophageal cancers (e.g. squamous cellcarcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach cancers(e.g. carcinoma, lymphoma, leiomyosarcoma), pancreatic cancers (e.g.ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoidtumors, vipoma), small bowel cancers (e.g. adenocarcinoma, lymphoma,carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma,neurofibroma, fibroma), large bowel cancers (e.g. adenocarcinoma,tubular adenoma, villous adenoma, hamartoma, leiomyoma);

genitourinary tract cancers, such as cancer of the kidney (e.g.adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia),bladder and urethra (e.g. squamous cell carcinoma, transitional cellcarcinoma, adenocarcinoma), prostate (e.g. adenocarcinoma, sarcoma),testis (e.g. seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, lipoma);

liver cancers, such as hepatoma (e.g. hepatocellular carcinoma),cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellularadenoma, hemangioma;

bone cancers, such as osteogenic sarcoma (e.g. osteosarcoma),fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing'ssarcoma, malignant lymphoma (e.g. reticulum cell sarcoma), multiplemyeloma, malignant giant cell tumor chordoma, osteochronfroma (e.gosteocartilaginous exostoses), benign chondroma, chondroblastoma,chondromyxofibroma, osteoid osteoma and giant cell tumors;

cancers of the head and/or nervous system, such as cancer of the skull(e.g. osteoma, hemangioma, granuloma, xanthoma, osteitis deformans),meninges (e.g. meningioma, meningiosarcoma, gliomatosis), brain (e.g.astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma),glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma,congenital tumors), spinal cord (e.g. neurofibroma, meningioma, glioma,sarcoma);

gynecological cancers, such as cancers of the uterus (e.g. endometrialcarcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia),ovaries (e.g. ovarian carcinoma (serous cystadenocarcinoma, mucinouscystadenocarcinoma, unclassified carcinoma), granulosa-thecal celltumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma),cancers of the vulva (e.g. squamous cell carcinoma, intraepithelialcarcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (e.g. clearcell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonalrhabdomyosarcoma)), fallopian tubes (e.g. carcinoma);

haematologic cancers, such as cancers of the blood and bone marrow (e.g.myeloid leukemia (acute and chronic), acute lymphoblastic leukemia,chronic lymphocytic leukemia, myeloproliferative diseases, multiplemyeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin'slymphoma (malignant lymphoma);

skin cancers, such as malignant melanoma, basal cell carcinoma, squamouscell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma,angioma, dermatofibroma, keloids; neurofibromatosis and Adrenal glands;and

neuroblastomas.

As used herein, references to cancerous cells and the like will includereferences to a cell afflicted by any one of the above identifiedconditions.

More particular cancers that may be mentioned include thosecorresponding to the cell lines used in the examples provided herein.

For example, particular cancers that may be mentioned include breastcancer (such as mammary adenocarcinoma, e.g. metastatic mammaryadenocarcinoma) and/or glioblastoma (such as glioblastoma multiform).

More particular cancers that may be mentioned include:

head and neck cancer (such as throat cancer, e.g. pharyngeal squamouscell carcinoma);

colon cancer (such as colorectal carcinoma);

skin cancer (such as epidermoid (skin) carcinoma);

gastrointestinal cancers (such as pancreatic cancer, e.g. pancreaticductal carcinoma);

breast cancer (such as mammary adenocarcinoma, e.g. metastatic mammaryadenocarcinoma);

lung cancer (such as carcinoma); and

haematologic cancers (such as leukemia, e.g. acute monocytic leukemia).

In particular embodiments, the cancer is a solid tumor cancer.

In more particular embodiments, the cancer is selected from pancreaticcancer, ovarian cancer and colorectal cancer.

For example, in certain embodiments, the cancer is selected fromcolorectal cancer (including those processing Ras mutations), small celllung cancer, non-small cell lung cancer (NSCLC), and glioma.

In other embodiments, the cancer is selected from non-small cell lungcancer, ovarian cancer, metastatic breast cancer, pancreatic cancer,hepatobiliary cancer (including hepatocellular cancer, bile duct cancerand cholangiocarcinoma), and gastric cancer.

In further embodiments, the cancer is selected from colorectal cancer(including Ras mutations), small cell lung cancer, non-small cell lungcancer, ovarian cancer, hepatobiliary cancer (including hepatocellularcancer, bile duct cancer and cholangiocarcinoma), gastric cancer,testicular cancer, and head and neck squamous cell carcinoma.

In certain embodiments of the present invention, the cancer is selectedfrom leukemia (including acute myeloid leukemia, acute lymphoblasticleukemia, chronic myeloid leukemia, and chronic lymphoid leukemia),lymphoma (including mantle cell lymphoma, Hodgkin's lymphoma andnon-Hodgkin's lymphoma), and prostate cancer

The skilled person will understand that treatment with compounds of theinvention may further comprise (i.e. be combined with) furthertreatment(s) for the same condition. In particular, treatment withcompounds of the invention may be combined with means for the treatmentof cancer, such as treatment with one or more other therapeutic agentthat is useful in the in the treatment of cancer and/or one or morephysical method used in the treatment of cancer (such as treatmentthrough surgery), as known to those skilled in the art.

In particular, treatment with compounds of the invention may beperformed in patients who are being or have been (i.e. as part or of atreatment for the same condition, such as within a month of treatmentwith compounds of the invention, such as within two weeks, e.g. within aweek or, particularly, on the same day) treated with a therapeutic agentor physical method that is capable of causing (e.g. can be demonstratedto cause) an increase in reactive oxygen species.

For the avoidance of doubt, the skilled person will understand thattherapeutic agents or physical methods capable of causing (e.g. can bedemonstrated to cause) an increase in reactive oxygen species may notnecessarily be effective treatments per se, but will become effectivewhen used in combination with compounds of the invention.

For the avoidance of doubt, the skilled person will understand thatcompounds of the invention may also be used in combination with one ormore other therapeutic agent that is useful in the in the treatment ofcancer and/or one or more physical method used in the treatment ofcancer (such as treatment through surgery) wherein such methods do notcause an increase in reactive oxygen species.

In particular, treatment with compounds of the invention may beperformed in patients who are being or have been treated withradiotherapy.

Thus, there is also provided:

a method of treating cancer in a patient in need thereof wherein thepatient is administered a therapeutically effective amount of a compoundof the invention in combination with treatment by radiotherapy (i.e.concomitantly or sequentially); and

a compound of the invention for use in treating cancer in a patient whois also being treated with radiotherapy.

Compounds of the invention will normally be administered orally,intravenously, subcutaneously, buccally, rectally, dermally, nasally,tracheally, bronchially, sublingually, intranasally, topically, by anyother parenteral route or via inhalation, in a pharmaceuticallyacceptable dosage form.

Compounds of the invention may be administered alone or may beadministered by way of known pharmaceutical compositions/formulations,including tablets, capsules or elixirs for oral administration,suppositories for rectal administration, sterile solutions orsuspensions for parenteral or intramuscular administration, and thelike.

According to a fourth aspect of the invention there is thus provided apharmaceutical composition/formulation comprising a compound of theinvention as hereinbefore defined (i.e. in the first aspect of theinvention, including all embodiments and particular features therein,but without the provisos), and optionally (e.g. in admixture with) oneor more pharmaceutically acceptable adjuvant, diluent and/or carrier.

In a particular embodiment of the fourth aspect of the invention, thecompound of the invention is a compound of the first aspect of theinvention (i.e. including the provisos).

The skilled person will understand that references herein to compoundsof the invention being for particular uses (and, similarly, to uses andmethods of use relating to compounds of the invention) may also apply topharmaceutical compositions comprising compounds of the invention asdescribed herein.

Compounds of the invention may be administered in the form of tablets orcapsules, e.g. time-release capsules that are taken orally.Alternatively, the compounds of the invention may be in a liquid formand may be taken orally or by injection. The compounds of the inventionmay also be in the form of suppositories, or, creams, gels, and foamse.g. that can be applied to the skin. In addition, they may be in theform of an inhalant that is applied nasally or via the lungs.

The skilled person will understand that compounds of the invention mayact systemically and/or locally (i.e. at a particular site).

Compounds of the invention may be administered orally, intravenously,subcutaneously, buccally, rectally, dermally, nasally, tracheally,bronchially, by any other parenteral route or via inhalation, in apharmaceutically acceptable dosage form. Alternatively, particularlywhere compounds of the invention are intended to act locally, compoundsof the invention may be administered topically.

Thus, in a particular embodiment, the pharmaceutical formulation isprovided in a pharmaceutically acceptable dosage form, including tabletsor capsules, liquid forms to be taken orally or by injection,suppositories, creams, gels, foams, or inhalants (e.g. to be appliedintranasally). For the avoidance of doubt, in such embodiments,compounds of the invention may be present as a solid (e.g. a soliddispersion), liquid (e.g. in solution) or in other forms, such as in theform of micelles.

In more particular embodiments, the pharmaceutical formulation isprovided the form of a tablets or capsules, liquid forms to be takenorally or by injection (e.g. a form suitable for intravenous injection).In particular, injection may take place using conventional means, andmay include the use of microneedles.

Depending on e.g. potency and physical characteristics of the compoundof the invention (i.e. active ingredient), pharmaceutical formulationsthat may be mentioned include those in which the active ingredient ispresent in at least 1% (or at least 10%, at least 30% or at least 50%)by weight. That is, the ratio of active ingredient to the othercomponents (i.e. the addition of adjuvant, diluent and carrier) of thepharmaceutical composition is at least 1:99 (or at least 10:90, at least30:70 or at least 50:50) by weight.

As described herein, compounds of the invention may also be combinedwith one or more other (i.e. different, e.g. agents other than compoundsof formula I) therapeutic agents that are useful in the treatment ofcancer. Such combination products that provide for the administration ofa compound of the invention in conjunction with one or more othertherapeutic agent may be presented either as separate formulations,wherein at least one of those formulations comprises a compound of theinvention, and at least one comprises the other therapeutic agent, ormay be presented (i.e. formulated) as a combined preparation (i.e.presented as a single formulation including a compound of the inventionand the one or more other therapeutic agent).

Thus, according to a fifth aspect of the invention, there is provided acombination product comprising:

(A) a compound of the invention as hereinbefore defined (i.e. in thefirst aspect of the invention, including all embodiments and particularfeatures therein, but without the provisos); and

(B) one or more other therapeutic agent that is useful in the treatmentof cancer, wherein each of components (A) and (B) is formulated inadmixture, optionally with one or more a pharmaceutically-acceptableadjuvant, diluent or carrier.

In a sixth aspect of the invention there is provided a kit-of-partscomprising:

(a) a pharmaceutical formulation as hereinbefore defined (i.e. in thefourth aspect of the invention); and

(b) one or more other therapeutic agent that is useful in the treatmentof cancer, optionally in admixture with one or morepharmaceutically-acceptable adjuvant, diluent or carrier,

which components (a) and (b) are each provided in a form that issuitable for administration in conjunction (i.e. concomitantly orsequentially) with the other.

In particular embodiments of the fourth and fifth aspects of theinvention, the compound of the invention is a compound of the firstaspect of the invention (i.e. including the provisos).

The skilled person will understand that compounds of the invention, andpharmaceutically-acceptable salts thereof, may be administered (forexample, as formulations as described hereinabove) at varying doses,with suitable doses being readily determined by one of skill in the art.Oral, pulmonary and topical dosages (and subcutaneous dosages, althoughthese dosages may be relatively lower) may range from between about 0.01μg/kg of body weight per day (μg/kg/day) to about 200 μg/kg/day,preferably about 0.01 to about 10 μg/kg/day, and more preferably about0.1 to about 5.0 μg/kg/day. For example, when administered orally,treatment with such compounds may comprise administration of aformulations typically containing between about 0.01 μg to about 2000mg, for example between about 0.1 μg to about 500 mg, or between 1 μg toabout 100 mg (e.g. about 20 μg to about 80 mg), of the activeingredient(s). When administered intravenously, the most preferred doseswill range from about 0.001 to about 10 μg/kg/hour during constant rateinfusion. Advantageously, treatment may comprise administration of suchcompounds and compositions in a single daily dose, or the total dailydosage may be administered in divided doses of two, three or four timesdaily (e.g. twice daily with reference to the doses described herein,such as a dose of 10 mg, 20 mg, 30 mg or 40 mg twice daily).

In any event, the physician, or the skilled person, will be able todetermine the actual dosage which will be most suitable for anindividual patient, which is likely to vary with the route ofadministration, the type and severity of the condition that is to betreated, as well as the species, age, weight, sex, renal function,hepatic function and response of the particular patient to be treated.The above-mentioned dosages are exemplary of the average case; therecan, of course, be individual instances where higher or lower dosageranges are merited, and such are within the scope of this invention.

Preparation of Compounds/Compositions

Pharmaceutical compositions/formulations, combination products and kitsas described herein may be prepared in accordance with standard and/oraccepted pharmaceutical practice.

Thus, in a further aspect of the invention there is provided a processfor the preparation of a pharmaceutical composition/formulation, ashereinbefore defined, which process comprises bringing into associationa compound of the invention, as hereinbefore defined, with one or morepharmaceutically-acceptable adjuvant, diluent or carrier.

In further aspects of the invention, there is provided a process for thepreparation of a combination product or kit-of-parts as hereinbeforedefined, which process comprises bringing into association a compound ofthe invention, as hereinbefore defined, or a pharmaceutically acceptablesalt thereof with the other therapeutic agent that is useful in thetreatment of cancer, and at least one pharmaceutically-acceptableadjuvant, diluent or carrier.

As used herein, references to bringing into association will mean thatthe two components are rendered suitable for administration inconjunction with each other.

Thus, in relation to the process for the preparation of a kit of partsas hereinbefore defined, by bringing the two components “intoassociation with” each other, we include that the two components of thekit of parts may be:

(i) provided as separate formulations (i.e. independently of oneanother), which are subsequently brought together for use in conjunctionwith each other in combination therapy; or

(ii) packaged and presented together as separate components of a“combination pack” for use in conjunction with each other in combinationtherapy.

Compounds of the invention as described herein may be prepared inaccordance with techniques that are well known to those skilled in theart, such as those described in the examples provided hereinafter.

According to a seventh aspect of the invention there is provided aprocess for the preparation of a compound of the first aspect of theinvention as hereinbefore defined (i.e. a compound of the invention butincluding the provisos), which process comprises:

(i) where n represents 2, reaction of a compound of formula IIA

wherein R¹, R² and R³ are as defined herein (i.e. for compounds of theinvention, or any particular feature or embodiment thereof) and LG¹represents a suitable leaving group (such as halo, e.g. chloro), with acompound of formula IIIA

wherein X is as defined herein (i.e. for compounds of the invention, orany particular feature or embodiments thereof) and M represents analkali metal ion (such as a Na ion), in the presence of a suitable acid(such as a concentrated acid, e.g. a concentrated mineral acid, forexample concentrated HCl, e.g. concentrated aqueous HCl) and in thepresence of a suitable solvent (such as a polar organic solvent, e.g.N,N′-dimethylacetamide, N,N′-dimethylformamide or tetrahydrofuran), andoptionally in the presence of a suitable phase transfer catalyst (suchas a quaternary ammonium salt, e.g. tetra-butyl ammonium chloride);

(ii) where n represents 2, particularly where at least one Y is presentand represents an electron-withdrawing group (such as —NO₂), reaction ofa compound of formula IIB

wherein R¹, R² and R³ are as defined herein (i.e. for compounds of theinvention, or any particular feature or embodiments thereof) and Mrepresents an alkali metal ion (such as a Na ion), with a compound offormula IIIB

wherein X is as defined herein in formula I (i.e. for compounds of theinvention, or any particular feature or embodiments thereof) and LG²represents a suitable leaving group (such as halo, e.g. chloro), in thepresence of a suitable acid (such as a concentrated acid, e.g. aconcentrated mineral acid, for example concentrated HCl, e.g.concentrated aqueous HCl) and in the presence of a suitable solvent(such as a polar organic solvent, e.g. N,N′-dimethylacetamide,N,N′-dimethylformamide or tetrahydrofuran), and optionally in thepresence of a suitable phase transfer catalyst (such as a quaternaryammonium salt, e.g. tetra-butyl ammonium chloride);

(iii) where n represents 2, reaction of a compound of formula IIA ashereinbefore defined with a compound of formula IIIA as hereinbeforedefined, in the presence of a suitable metal halide (such as a suitablemetal iodide, e.g. CuI, or a suitable metal bromide, e.g. CuBr; whichmetal halide may be present in excess, such as in amount correspondingto at least 2 molar equivalents of the compound of formula IIA and/orthe compound of formula IIIA) and in the presence of a suitable solvent(such as a polar organic solvent, e.g. N,N′-dimethylacetamide,N,N′-dimethylformamide, tetrahydrofuran or3-dimethyl-2-imidazolidinone), under conditions known to those skilledin the art;

(iv) where n represents 2, reaction of a compound of formula IIB ashereinbefore defined (particularly where at least one R⁴ is present andrepresents an electron-withdrawing group, such as —NO₂) with a compoundof formula IIIB as hereinbefore defined, in the presence of a suitablemetal halide (such as a suitable metal iodide, e.g. CuI, or a suitablemetal bromide, e.g. CuBr; which metal halide may be present in excess,such as in amount corresponding to at least 2 molar equivalents of thecompound of formula IIB and/or the compound of formula IIIB) and in thepresence of a suitable solvent (such as a polar organic solvent, e.g.N,N′-dimethylacetamide, N,N′-dimethylformamide, tetra-hydrofuran or3-dimethyl-2-imidazolidinone), under conditions known to those skilledin the art;

(v) reaction of a compound of formula IV

wherein R¹ to R³ and X are as defined herein (i.e. for compounds of theinvention, or any particular feature or embodiments thereof), with asuitable oxidising agent (i.e. an oxidising agent chosen and used in amanner as required to achieved the desired degree of oxidation; such asa hypochlorite salt, e.g. sodium hypochlorite, a peroxymonosulfate salt,e.g. potassium peroxymonosulfate (Oxone), a percarboxylic acid, e.g.meta-chloroperoxybenzoic add (mCPBA), or potassium permanganate) in thepresence of a suitable solvent (such as a polar organic solvent, e.g.N,N′-dimethylacetamide, N,N′-dimethylformamide or terahydrofuran), andoptionally in the presence of water, under conditions known to thoseskilled in the art;

(vi) where n represents 2, particularly where one or more Y is presentand represents an electron donating group (such as an alkyl group),reaction of a compound of formula V

wherein R¹, R² and R³ are as defined herein (i.e. for compounds of theinvention, or any particular feature or embodiments thereof) and LG³represents a suitable leaving group (such as halo, e.g. chloro) with acompound of formula VI

wherein X is as defined (i.e. for compounds of the invention, or anyparticular feature or embodiments thereof), in the presence of asuitable Lewis acid (such as AlCl₃) and in the presence of a suitablesolvent (such as an organic solvent, e.g. dichloromethane ordichloroethane);

(vii) where n represents 2, reaction of a compound of formula V asdefined herein with a compound of formula VI as defined herein (forexample, where one or more Y group is present in the alpha positionrelative to the point of attachment to the sulfonyl group and representsa suitable directing group), in the presence of a suitable catalyst(such as palladium(II) acetate) and a suitable base (such as a alkalimetal carbonate, e.g. potassium carbonate), and in the presence of asuitable solvent (such as an organic solvent, e.g. dichloromethane);

(viii) where n represents 2, reaction of a compound of formula V asdefined herein with a compound of formula VII

wherein X is as defined herein (i.e. for compounds of the invention, orany particular feature or embodiments thereof) and LG⁴ represents asuitable leaving group (such as a boronic acid), in the presence of asuitable catalyst (such as a suitable metal halide, e.g. CuBr, orphenanthroline) and in the presence of a suitable solvent (such as anorganic solvent, e.g. dichloromethane or dichloroethane); or

(ix) where n represents 2, reaction of a compound of formula IIB asdefined herein with (a) a compound of formula VI as defined hereinhaving at least one Y group, or (b) a compound of formula VI as definedherein but having a group that may be converted to a Y group, whereinthe Y group or group that may be converted to a Y group is present inthe alpha position relative to the essential H substituent andrepresents a suitable directing group (such as a suitable amide, e.g.—C(O)N(H)C(CH₃)₂-2-pyridinyl), in the presence of a suitable catalystand/or oxidant (such as copper(II) acetate and/or silver carbonate), andin the presence of a suitable solvent (such as an organic solvent, e.g.dichloroethane), which step may further comprise conversion of the groupthat may be converted to a Y group to the required Y group, underconditions known to those skilled in the art.

Compounds of formulae IIA, IIB, IIIA, IIIB, IV, V, VI and VII are eithercommercially available, are known in the literature, or may be obtainedeither by analogy with the processes described herein, or byconventional synthetic procedures, in accordance with standardtechniques, from available starting materials using appropriate reagentsand reaction conditions. In this respect, the skilled person may referto inter alia “Comprehensive Organic Synthesis” by B. M. Trost and I.Fleming, Pergamon Press, 1991. Further references that may be employedinclude “Heterocyclic Chemistry” by J. A. Joule, K. Mills and G. F.Smith, 3^(rd) edition, published by Chapman & Hall, “ComprehensiveHeterocyclic Chemistry II” by A. R. Katritzky, C. W. Rees and E. F. V.Scriven, Pergamon Press, 1996 and “Science of Synthesis”, Volumes 9-17(Hetarenes and Related Ring Systems), Georg Thieme Verlag, 2006.

In particular, compounds of formula IV may be prepared by reaction of acompound of formula VIII

wherein X is as defined herein (i.e. for compounds of the invention, orany particular feature or embodiments thereof), with a compound offormula IIA as herein before defined, under conditions known to thoseskilled in the art, such as in the presence of a suitable base (such asa metal carbonate, e.g. potassium carbonate, a metal hydroxide, e.g.sodium hydroxide, or an amine base, e.g. triethyl amine), and in thepresence of a suitable solvent (such as a polar organic solvent, e.g.N,N′-dimethylacetamide, N,N′-dimethylformamide or tetrahydrofuran, or amixture of a polar organic solvent and water), under conditions known tothose skilled in the art.

Similarly, compounds of formula IV (particularly where at least one Y ispresent and represents an electron-withdrawing group, such as —NO₂) maybe prepared by reaction of a compound of formula IX

wherein R¹, R² and R³ are as defined herein (i.e. for compounds of theinvention, or any particular feature or embodiments thereof), with acompound of formula IIIB as described herein, under conditions known tothose skilled in the art (for example, where the R⁴ groups present inthe compound of formula IIIB are not sufficiently electron withdrawing,the reaction may be performed in the presence of a suitable catalyst,such as palladium(II) acetate or copper oxide, in which case thesuitable base may be an alkali metal tert-butoxide, such as Kt-OBu).

Similarly, compounds of formulae VIII and IX are either commerciallyavailable, are known in the literature, or may be obtained either byanalogy with the processes described herein, or by conventionalsynthetic procedures, in accordance with standard techniques, fromavailable starting materials using appropriate reagents and reactionconditions.

The substituents R¹ to R³ and Y (or, when the compound of formula I isdefined as a compound of formula Ia, the substituents R¹ to R⁹), ashereinbefore defined, may be modified one or more times, after or duringthe processes described above for preparation of compounds of formula I(including compounds of formula Ia) by way of methods that are wellknown to those skilled in the art. Examples of such methods includesubstitutions, reductions, oxidations, dehydrogenations, alkylations,dealkylations, acylations, hydrolyses, esterifications, etherifications,halogenations and nitrations. The precursor groups can be changed to adifferent such group, or to the groups defined in formula I, at any timeduring the reaction sequence. The skilled person may also refer to“Comprehensive Organic Functional Group Transformations” by A. R.Katritzky, O. Meth-Cohn and C. W. Rees, Pergamon Press, 1995 and/or“Comprehensive Organic Transformations” by R. C. Larock, Wiley-VCH,1999.

Compounds of the invention may be isolated from their reaction mixturesand, if necessary, purified using conventional techniques as known tothose skilled in the art. Thus, processes for preparation of compoundsof the invention as described herein may include, as a final step,isolation and optionally purification of the compound of the invention.

It will be appreciated by those skilled in the art that, in theprocesses described above and hereinafter, the functional groups ofintermediate compounds may need to be protected by protecting groups.The protection and deprotection of functional groups may take placebefore or after a reaction in the above-mentioned schemes.

Protecting groups may be applied and removed in accordance withtechniques that are well known to those skilled in the art and asdescribed hereinafter. For example, protected compounds/intermediatesdescribed herein may be converted chemically to unprotected compoundsusing standard deprotection techniques. The type of chemistry involvedwill dictate the need, and type, of protecting groups as well as thesequence for accomplishing the synthesis. The use of protecting groupsis fully described in “Protective Groups in Organic Synthesis”, 3rdedition, T. W. Greene & P. G. M. Wutz, Wiley-Interscience (1999).

In a further aspect of the invention, there is provided a compound offormula IV as defined herein (i.e. wherein R¹, R², R³ and X are asdefined herein, including all particular features and embodimentsthereof), or a pharmaceutically acceptable salt thereof.

Particular compounds of formula IV that may be mentioned include thoseprepared in the examples provided herein, and pharmaceuticallyacceptable salts thereof.

Compounds of the invention may have the advantage that they may be moreefficacious than, be less toxic than, be longer acting than, be morepotent than, produce fewer side effects than, be more easily absorbedthan, and/or have a better pharmacokinetic profile (e.g. higher oralbioavailability and/or lower clearance) than, and/or have other usefulpharmacological, physical, or chemical properties over, compounds knownin the prior art, whether for use in the above-stated indications orotherwise. In particular, compounds of the invention may have theadvantage that they are more efficacious and/or exhibit advantageousproperties in vivo.

Without wishing to be bound by theory, it is thought that inhibition ofthioredoxin reductase is obtained by the utilization of strongelectrophilicity of small molecule inhibitors in combination with apronounced inherent nucleophilicity of NADPH-reduced, but not oxidized,thioredoxin reductase, resulting in selective and potent inhibition ofsaid enzyme without major targeting of other cellular pathways orenzymes.

Moreover, it is thought that normal non-cancerous cells may survivewithout a functional cytosolic thioredoxin reductase enzyme because ofmaintained function of the glutathione system, while cancer cells cannotsurvive upon specific inhibition of cytosolic thioredoxin reductase.

EXAMPLES

The invention is illustrated by way of the following examples, in whichthe following abbreviations may be employed.

-   aq aqueous-   BSA bovine serum albumin-   conc concentrated-   DMA N,N′-dimethylacetamide-   DMF N,N′-dimethylformamide-   DMSO dimethyl sulfoxide-   DTNB 5,5′-dithio-bis-(2-nitrobenzoic acid)-   EDTA ethylenediaminetetraacetic add-   GSSG glutathione disulfide-   HPLC high performance liquid chromatography-   HRMS high resolution mass spectrometry-   mCPBA meta-chloroperbenzoic acid-   NADPH nicotinamide adenine dinucleotide phosphate-   NMR nuclear magnetic resonance-   PBS phosphate buffered saline-   rt room temperature

Starting materials and chemical reagents specified in the synthesesdescribed below are commercially available from a number of suppliers,such as Sigma Aldrich.

In the event that there is a discrepancy between nomenclature and thestructure of compounds as depicted graphically, it is the latter thatpresides (unless contradicted by any experimental details that may begiven and/or unless it is clear from the context). The names of thefinal compounds may be translated to the structures e.g. usingChemBioDraw Ultra 14.

Example 1: 6-Methoxy-3-nitro-2-(pyridin-2-ylsulfonyl)pyridine

(a) 6-Methoxy-3-nitro-2-(pyridin-2-ylthio)pyridine

A mixture of 2-chloro-6-methoxy-3-nitropyridine (0.25 g, 1.33 mmol),2-mercaptopyridine (0.16 g, 1.46 mmol), K₂CO₃ (0.22 g, 1.62 mmol) andDMF (1 mL) was stirred at rt for 0.5 h. The mixture was poured intowater and filtered to give the sub-title compound (0.34 g, 98%).

(b) 6-Methoxy-3-nitro-2-(pyridin-2-ylsulfonyl)pyridine

NaOCl (aq, 10%, 1.71 mL, 2.86 mmol) was added dropwise to a stirredmixture of 6-methoxy-3-nitro-2-(pyridin-2-ylthio)pyridine (0.34 g, 1.30mmol), glacial acetic acid (0.10 mL, 1.67 mmol) and DMF (1 mL) at rt.The mixture was stirred at rt for 4 h and poured into water. The pH wasadjusted to ˜9 with aq NaOH (20% (w/v)). After stirring for 30 secondsthe precipitate was collected and washed with water. The solid wasrecrystallized from H₂O/EtOH (4:1) to give the title compound (0.12 g,31%).

¹H NMR (400 MHz, CDCl₃) δ8.74-8.67 (1H, m), 8.31-8.24 (2H, m), 8.08-8.00(1H, m), 7.61-7.54 (1H, m), 7.01-6.96 (1H, m), 3.65 (3H, s);

¹³C-NMR (100 MHz, CDCl₃) δ164.2, 157.4, 150.3, 150.2, 138.1, 136.9,127.5, 124.0, 115.3, 55.2;

ESI-MS: 296 [M+H]⁺.

Example 2: 6-Chloro-3-nitro-2-(pyridin-2-ylsulfonyl)pyridine

(a) 6-Chloro-5-nitropyridin-2-amine

Conc. HNO₃ (2.39 mL, 35.00 mmol) was added dropwise to a mixture of concH₂SO₄ (56 mL, 1050 mmol) and 6-chloropyridin-2-amine (3.00 g, 23.34mmol) at 0° C. The mixture was stirred at 0° C. for 4 h and poured intoice-water. The mixture was extracted with EtOAc (3×100 mL). The combinedorganic layers were dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by chromatography to give the sub-title compound(1.38 g, 34%).

(b) 5-Nitro-6-(pyridin-2-ylthio)pyridin-2-amine

A mixture of 6-chloro-5-nitropyridin-2-amine (0.26 g, 1.50 mmol),2-mercaptopyridine (0.18 g, 1.65 mmol), K₂CO₃ (0.25 g, 1.83 mmol) andDMF (2.1 mL) was stirred at 80° C. for 3.5 h. The mixture was pouredinto water and extracted with CH₂Cl₂ (3×15 mL). The combined organiclayers were dried over anhydrous Na₂SO₄ and concentrated. The residuewas dissolved in CH₂Cl₂, and the product was precipitated by addition ofhexane to give the sub-title compound (0.27 g, 73%).

(c) 6-Chloro-3-nitro-2-(pyridin-2-ylthio)pyridine

Isoamylnitrite (0.26 mL, 1.93 mmol) was added to a stirred mixture of5-nitro-6-(pyridin-2-ylthio)pyridin-2-amine (0.24 g, 0.97 mmol), CuCl₂(0.26 g, 1.93 mmol) and MeCN (5 mL) at rt. The mixture was stirred at60° C. for 14 h, poured into acidic water (1N HCl, 4 mL) and extractedwith EtOAc (3×15 mL). The combined organic layers were washed withsaturated aq NaHCO₃ (10 mL), brine (10 mL) and dried over anhydrousNa₂SO₄ and concentrated. The residue was purified by chromatography togive the sub-title compound (0.08 g, 32%).

(d) 6-Chloro-3-nitro-2-(pyridin-2-ylsulfonyl)pyridine

mCPBA (0.17 g, 0.67 mmol) was added in portions to a stirred mixture of6-chloro-3-nitro-2-(pyridin-2-ylthio)pyridine (0.08 g, 0.31 mmol) andCH₂Cl₂ (8 mL) at 0° C. The mixture was stirred at rt for 14 h and pouredinto saturated aq Na₂S₂O₃ (3 mL) at 0° C. The phases were separated andthe organic layer extracted with saturated aq NaHCO₃ (2×5 mL) and brine(5 mL). The organic phase was dried over anhydrous Na₂SO₄ andconcentrated. The crude mixture was purified by chromatography to givethe title compound (0.03 g, 29%).

¹H NMR (400 MHz, CDCl₃) δ8.67 (ddd, J=4.7, 1.7, 0.9 Hz, 1H), 8.27 (dt,J=7.9, 1.0 Hz, 1H), 8.24 (d, J=8.4 Hz, 1H), 8.06 (td, J=7.8, 1.7 Hz,1H), 7.70 (d, J=8.4 Hz, 1H), 7.59 (ddd, J=7.7, 4.7, 1.1 Hz, 1H);

¹³C-NMR (100 MHz, CDCl₃) δ 156.7, 153.7, 150.6, 150.3, 144.5, 138.3,136.1, 129.2, 128.0, 123.8;

ESI-MS: 300 [M+H]⁺.

Example 3: 6-Dimethylamino-3-nitro-2-(pyridin-2-ylsulfonyl)pyridine

(a) 6-Chloro-N,N-dimethylpyridin-2-amine

A mixture of 2,6-dichloropyridine (2.20 g, 14.9 mmol) and DMF (11.5 mL,148.7 mmol) was heated under microwave irradiation at 180° C. for 1 h.The mixture was poured into water and extracted with EtOAc (3×30 mL).The combined organic phases were dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by chromatography to give thesub-title compound (2.12 g, 91%).

(b) 6-Chloro-N,N-dimethyl-5-nitropyridin-2-amine

Conc HNO₃ (0.9 mL, 13.52 mmol) was added dropwise to a mixture of concH₂SO₄ (32.4 mL, 608.6 mmol) and 6-chloro-N,N-dimethylpyridin-2-amine(2.12 g, 13.5 mmol) at 0° C. The mixture was stirred at 0° C. for 1.5 hand poured into ice-water. The mixture was extracted with CH₂Cl₂ (3×100mL). The combined organic layers were washed with saturated aq Na₂CO₃,dried over anhydrous Na₂SO₄ and concentrated. The residue was purifiedby chromatography to give the sub-title compound (0.89 g, 33%).

(c) N,N-Dimethyl-5-nitro-6-(pyridin-2-ylthio)pyridin-2-amine

A mixture of 6-chloro-N,N-dimethyl-5-nitropyridin-2-amine (0.11 g, 0.55mmol), 2-mercaptopyridine (0.07 mg, 0.61 mmol), K₂CO₃ (0.09 g, 0.67mmol) and DMF (1 mL) was stirred at 80° C. for 1 h. The mixture waspoured into water (150 mL), the precipitate was collected, washed withwater and dried to give the sub-title compound (0.12 g, 76%).

(d) 6-Dimethylamino-3-nitro-2-(pyridin-2-ylsulfonyl)pyridine

mCPBA (0.22 g, 0.92 mmol) was added in portions to a stirred mixture ofN,N-dimethyl-5-nitro-6-(pyridin-2-ylthio)pyridin-2-amine (0.12 g, 0.42mmol) and CH₂Cl₂ (8 mL) at 0° C. The mixture was stirred at rt for 5 hand poured into saturated aq K₂CO₃ (5 mL). The phases were separated andthe aq layer extracted with CH₂Cl₂. The combined organic phases werewashed with saturated aq Na₂S₂O₅ and NaHSO₃ mixture, dried overanhydrous Na₂SO₄ and concentrated. The residue was recrystallized fromH₂O/EtOH (1:9) and additionally purified by chromatography to give thetitle compound (0.06 g, 44%).

¹H NMR (400 MHz, CDCl₃) δ8.74-8.68 (1H, m), 8.27-8.23 (1H, m), 8.21 (1H,d, J=9.4 Hz), 8.03-7.96 (1H, m), 7.55-7.49 (1H, m), 6.54 (1H, d, J=9.4Hz), 2.90 (6H, br s);

¹³C-NMR (100 MHz, CDCl₃) δ 158.2, 157.9, 152.4, 149.9, 137.8, 136.0,126.9, 124.0, 107.2, 38.2;

ESI-MS: 309 [M+H]⁺.

The following example compounds where prepared from2-chloro-6-methoxy-3-nitropyridine and the appropriate heteroarylthiolin accordance with the procedure in Example 1, Step a, and Example 2,Step d.

Chemical structure MS [m/z (M + H)⁺] Name ¹H-NMR [solvent, δ] Ex.¹³C-NMR [solvent, δ] 4

MS [m/z (M + H)⁺ = (Calculated for C₁₁H₉N₃O₅S + H: 296.04) found: 296.1]6-methoxy-3-nitro-2-(pyridin-4-ylsulfonyl)pyridine ¹H-NMR [DMSO-d₆, δ8.51 (d, J = 8 Hz, 1H), 8.29 (d, J = 7 Hz, 2H), 7.82 (d, J = 7 Hz, 2H),7.16 (d, J = 8 Hz, 1H), 4.09 (s, 3H)] 5

MS [m/z (M + H)⁺ = (Calculated for C₁₀H₈N₄O₅S + H: 297.03) found: 297.1]2-((6-methoxy-3-nitropyridin-2-yl)sulfonyl)pyrimidine ¹H-NMR [CDCl₃, δ8.93 (d, J = 5 Hz, 2H), 8.38 (d, J = 9 Hz, 1H), 7.55 (t, J = 5 Hz, 1H),7.06 (d, J = 9 Hz, 1H), 3.87 (s, 3H)] 6

MS [m/z (M + H)⁺ = (Calculated for C₉H₈N₄O₅S + H: 285.03) found: 385.1]2-((1H-imidazol-2-yl)sulfonyl)-6-methoxy-3-nitropyridine ¹H-NMR[DMSO-d₆, δ 14.09 (s, 1H), 8.54 (d, J = 9 Hz, 1H), 7.63-7.28 (m, 3H),3.55 (s, 3H)] 7

MS [m/z (M + H)⁺ = (Calculated for C₁₀H₉N₃O₅S₂ + H: 316.01) found:315.8] 2-((6-methoxy-3-nitropyridin-2-yl)sulfonyl)-4-methylthiazole¹H-NMR [CDCl₃, δ 8.30 (d, J = 9 Hz, 1H), 7.41 (s, 1H), 6.98 (d, J = 9Hz, 1H), 3.60 (s, 3H), 2.55 (s, 3H)]

Example 8: 6-Methoxy-3-nitro-2-(pyridin-2-ylsufinyl)-pyridine

(a) 6-Methoxy-3-nitro-2-(pyridin-2-ylsulfanyl)-pyridine

To a solution of 6-methoxy-2-chloro-3-nitro pyridine (5 g, 26.59 mmol)in dimethylformamide (50 mL) was added potassium carbonate (4.40 g,31.91 mmol) and 2-mercapto pyridine (3.62 g, 29.25 mmol) at roomtemperature. The reaction mixture was stirred overnight at roomtemperature. Progress of reaction was monitored by LCMS. The reactionmixture was quenched with ice cold water (10 mL) and was extracted withethyl acetate (100 mL). The organic layer was washed with water (3×20mL) followed by brine (1×30 mL). The organic layer was dried overanhydrous sodium sulphate and was evaporated under reduced pressure togive the crude product which was purified by column chromatographyeluting with 5% ethyl acetate in hexane affording the sub-title compoundas yellow solid (3 g, 42.85%).

¹H NMR (CDCl₃, 400 MHz) δ 8.72 (d, J=3.4 Hz, 1H), 8.39 (d, J=8.9 Hz,1H), 7.79-7.75 (m, 1H), 7.68 (d, J=7.7 Hz, 1H), 7.35-7.33 (m, 1H), 6.49(d, J=9.0 Hz, 1H), 3.32 (s, 3H); LCMS [m/z (M+H)⁺] 264 (MW calc=263),R_(t)=1.83

(b) 6-methoxy-3-nitro-2-(pyridin-2-ylsufinyl)-pyridine

To a solution of 6-methoxy-3-nitro-2-(pyridin-2-ylsulfanyl)-pyridine(1.5 g, 57.03 mmol) in dichloromethane (30 mL) was addedm-chloroperbenzoic acid (1.47 g, 85.55 mmol) at room temperature. Thereaction mixture was stirred at room temperature overnight. Progress ofreaction was monitored by LCMS. The reaction mixture was diluted withdichloromethane (20 mL) and washed with saturated sodium sulphitesolution (2×20 mL) followed by brine (1×20 mL). The organic layer wasdried over anhydrous sodium sulphate and was evaporated under reducedpressure to give the crude product which was purified by columnchromatography eluting with 20% ethyl acetate in hexane affording thetitle compound as yellow solid (1.59 g, 37.67%).

¹H NMR (DMSO-d₆, 400 MHz) δ 8.59-8.51 (m, 2H), 8.06 (d, J=7.5 Hz, 1H),7.97 (d, J=7.7 Hz, 1H), 7.52 (d, J=6.0 Hz, 1H), 7.18 (d, J=8.9 Hz, 1H),3.97 (s, 3H); LCMS [m/z (M+H)⁺] 280 (MW calc=279); R_(t)=1.56; HPLCpurity at λ=210 nm: 99.05%.

BIOLOGICAL EXAMPLES Biological Example 1: Inhibition of RecombinantTrxR1 and GR

Small molecule inhibition of recombinant thioredoxin reductase 1 (TrxR1)and gluthathione reductase (GR) was examined in 96-well plate format. 30nM TrxR1 was incubated in the presence of 250 μM NADPH, 0.1 mg/ml BSA,and various concentrations of the compounds (1% DMSO final) in 50 mMTris (pH 7.5) and 2 mM EDTA buffer for 15 minutes. Following theincubation period, 2 mM DTNB was added to each well and the change inO.D. at 412 nm was followed. Percent activity was determined using DMSOvehicle and no TrxR1 (blank) controls. 2 nM GR was incubated in thepresence of 250 μM NADPH, 0.1 mg/ml BSA, and various concentrations ofcompounds (1% DMSO final) in 50 mM Tris (pH 7.5) and 2 mM EDTA bufferfor 15 minutes. Following the incubation period, 1 mM GSSG was added toeach well and the change in O.D. at 340 nm was followed. Percentactivity was determined using DMSO vehicle and no GR (blank) controls.

Using the assays described in Biological Example 1, the following IC₅₀values were obtained. The results obtained are provided in Table 1below.

TrxR GR inhibition inhibition Example (nM) (μM) 1 26.8 64.19 2 56.9 9.893 558 >100 μM 4 0.854 11.17 5 10.8 >100 μM 6 3.99 >100 μM 7 6.90 >100 μM8 5.50 —

Biological Example 2: Head and Neck Cancer Cell Viability Assay

FaDu cells were plated 2000 cells/well in 96-well black optical platesin the presence of 10% FBS media containing 25 nM selenite. Thefollowing day cells were treated with various concentrations of thecompound of Example 1 (0.1% DMSO final) and incubated for 72 hrs. Afterthe incubation Cell-Quanti Blue reagent was added to each well andincubated for additional 3 hrs. Fluorescence was read ex: 530 nm/em: 590nm, and percent of viability was determined using DMSO vehicle and nocell (blank) controls.

Using the assays described in Biological Example 2, the following IC₅₀values were obtained. The results obtained are provided in Table 2below.

FaDu Cell IC50 Example (μM) 1 1.61 2 0.61 3 2.89 7 45.71

Bioloical Example 3: Breast Cancer Cell Viability Assay

MDA-MB-231 cells were plated 2000 cells/well in 96-well black opticalplates in the presence of 10% FBS media containing 25 nM selenite. Thefollowing day cells were treated with various concentrations ofcompounds (0.1% DMSO final) and incubated for 72 hrs. After theincubation Alamar Blue reagent was added to each well and incubated foradditional 3 hrs. Fluorescence was read ex: 530 nm/em: 590 nm, andpercent of viability was determined using DMSO vehicle and no cell(blank) controls.

Using the assays described in Biological Example 3, the following IC₅₀values were obtained. The results obtained are provided in Table 3below.

MDA-MB-231 Cell viability IC50 Example (μM) 1 3.61 4 >100 μM 5 4.54 610.85 7 3.09

Biological Example 4: Cancer Cell Viability Assay

Breast cancer and glioblastoma cell lines were plated 4000 cells/well in96-well plates in the presence of 10% FBS media. The following day cellswere treated with various concentrations of example compounds (0.1% DMSOfinal) and incubated for 72 hrs. After the incubation An MTT assay wasperformed to access cell viability. Percent of viability was determinedusing DMSO vehicle and no cell (blank) controls.

Using the assays described in Biological Example 4, the following IC₅₀values were obtained. The results obtained are provided in Table 4below.

U-87 MDA-MB-231 MDA-MB-468 MG IC50 IC50 IC50 Example (μM) (μM) (μM) 18.2 2.97 4.34 8 2.53 1.02 0.96

The invention claimed is:
 1. A compound of formula I

or a pharmaceutically acceptable salt thereof, wherein: L represents—S(O)_(n)—; n represents 2 or 1; X represents a heteroaryl group,attached to L via a carbon atom, optionally substituted by one or moregroups independently selected from Y; R¹, R² and R³ each independentlyrepresent H, halo, R^(a1), —CN, -A^(a1)-C(Q^(a1))R^(b1),-A^(b1)-C(Q^(b1))N(R^(c1))R^(d1), -A^(c1)-C(Q^(c1))OR^(e1),-A^(d1)-S(O)_(p)R^(f1), -A^(e1)-S(O)_(p)N(R^(g1))R^(h1),-A^(f1)-S(O)_(p)OR^(i1), —N₃, —N(R^(j1))R^(k1), —N(H)CN, —NO₂, —ONO₂,—OR^(l1) or —SR^(m1); each A^(a1) to A^(f1) independently represents asingle bond, —N(R^(p1))— or —O—; each Q^(a1) to Q^(c1) independentlyrepresents ═O, ═S, ═NR^(n1) or ═N(OR^(o1)); each R^(a1) and R^(f1)independently represents C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl eachoptionally substituted by one or more groups independently selected fromG^(1a), heterocyclyl optionally substituted by one or more groupsindependently selected from G^(1b), aryl optionally substituted by oneor more groups independently selected from G^(1c), or heteroaryloptionally substituted by one or more groups independently selected fromG^(1d); each R^(b1), R^(c1), R^(d1), R^(e1), R^(g1), R^(h1), R^(i1),R^(j1), R^(k1), R^(l1), R^(m1), R^(n1), R^(o1) and R^(p1) independentlyrepresents H, C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl each optionallysubstituted by one or more groups independently selected from G^(1a),heterocyclyl optionally substituted by one or more groups independentlyselected from G^(1b), aryl optionally substituted by one or more groupsindependently selected from G^(1c), or heteroaryl optionally substitutedby one or more groups independently selected from G^(1d); any of R^(c1)and R^(d1), R^(g1) and R^(h1) and/or R^(j1) and R^(k1) are linkedtogether to form, together with the nitrogen atom to which they areattached, a 3-to 6-membered ring, which ring optionally contains onefurther heteroatom and which ring optionally is substituted by one ormore groups independently selected from halo, and C₁₋₃ alkyl, C₂₋₃alkenyl or C₂₋₃ alkynyl each optionally substituted by one or more halo,and ═O; each G^(1a) and G^(1b) independently represents halo, —CN,—N(R^(a2))R^(b2), —OR^(c2), —SR^(d2) or ═O; each G^(1c) and G^(1d)independently represents halo, —CN, —N(R^(a2))R^(b2), —OR^(c2) or—SR^(d2); each R^(a2), R^(b2), R^(c2) and R^(d2) independentlyrepresents H or C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl each optionallysubstituted by one or more fluoro; or R^(a2) and R^(b2) are linkedtogether to form, along with the nitrogen atom to which they areattached, a 3- to 6-membered ring, which ring optionally contains onefurther heteroatom and which ring optionally is substituted by one ormore groups independently selected from fluoro, C₁₋₃ alkyl, C₂₋₃ alkenylor C₂₋₃ alkynyl each optionally substituted by one or more fluoro; eachY independently represents halo, R^(a3), —CN, -A^(a2)-C(Q^(a2))R^(b3),-A^(b2)-C(Q^(b2))N(R^(c3))R^(d3), -A^(c2)-C(Q^(c2))OR^(e3),-A^(d2)-S(O)_(q)R^(f3), -A^(e2)-S(O)_(q)N(R^(g3))R^(h3),-A^(f2)-S(O)_(q)OR^(i3), —N₃, —N(R^(j3))R^(k3), —N(H)CN, —ONO₂, —OR¹³ or—SR^(m3); each Q^(a2) to Q^(c2) independently represents ═O, ═S,═NR^(n3) or ═N(OR^(o3)); each A^(a2) to A^(r2) independently representsa single bond, —N(R^(p3))— or —O—; each R^(a3) and R^(f1) independentlyrepresents C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl each optionallysubstituted by one or more groups independently selected from G^(2a),heterocyclyl optionally substituted by one or more groups independentlyselected from G^(2b), aryl optionally substituted by one or more groupsindependently selected from G^(2c), or heteroaryl optionally substitutedby one or more groups independently selected from G^(2d); each R^(b3),R^(c3), R^(d3), R^(e3), R^(g3), R^(h3)R^(i3), R^(j3), R^(k3), R^(l3),R^(m3), R^(n3), R^(o3) and R^(p3) independently represents H, C₁₋₆alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl each optionally substituted by oneor more groups independently selected from G^(2a), heterocyclyloptionally substituted by one or more groups independently selected fromG^(2b), aryl optionally substituted by one or more groups independentlyselected from G^(2c), or heteroaryl optionally substituted by one ormore groups independently selected from G^(2d); or any two R^(c3) andR^(d3), R^(g3) and R^(h3) and/or R^(j3) and R^(k3) are linked togetherto form, along with the nitrogen atom to which they are attached, a 3-to6-membered ring, which ring optionally contains one further heteroatomand which ring optionally is substituted by one or more groupsindependently selected from heterocyclyl optionally substituted by oneor more groups independently selected from G^(2b), aryl optionallysubstituted by one or more groups independently selected from G^(2c), orheteroaryl optionally substituted by one or more groups independentlyselected from G^(2d), and ═O; each G^(2a) independently represents halo,—CN, —N(R^(j4))R^(k4), —OR^(l4), —SR^(m4) or ═O; each G^(2b)independently represents halo, R^(a4), —CN, —N(R^(j4))R^(k4), —OR^(l4),—SR^(m4) or ═O; each G^(2C) and G^(2d) independently represents halo,R^(a4), —CN, -A^(a3)-C(Q^(a3))R^(b4), -A^(b3)-C(Q^(b3))N(R^(c4))R^(d4),-A^(c3)-C(Q^(c3))OR^(e4), -A^(d3)-S(O)_(q)R^(f4),-A^(e3)-S(O)_(q)N(R^(g4))R^(h4), -A^(f3)-S(O)_(q)OR¹⁴, —N₃,—N(R^(j4))R^(k4), —N(H)CN, —NO₂, —ONO₂, —OR¹⁴ or —SR^(m4); each Q^(a3)to Q^(c3) independently represents ═O, ═S, ═NR^(n4) or ═N(OR^(o4)); eachA^(a3) to A¹³ independently represents a single bond, —N(R^(p4))— or—O—; each R^(a4) and R^(f4) independently represents C₁₋₆ alkyl, C₂₋₆alkenyl or C₂₋₆ alkynyl each optionally substituted by one or moregroups independently selected from G^(3a), heterocyclyl optionallysubstituted by one or more groups independently selected from G^(3b),aryl optionally substituted by one or more groups independently selectedfrom G^(3c), or heteroaryl optionally substituted by one or more groupsindependently selected from G^(3d); each R^(b4), R^(c4), R^(d4), R^(e4),R^(g4), R^(h4), R^(i4), R^(j4), R^(k4), R^(l4), R^(m4), R^(n4), R^(o4)and R^(p4) independently represents H, C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆alkynyl each optionally substituted by one or more groups independentlyselected from G^(3a) or heterocyclyl optionally substituted by one ormore groups independently selected from G^(3b), aryl optionallysubstituted by one or more groups independently selected from G^(3c), orheteroaryl optionally substituted by one or more groups independentlyselected from G^(3d); or any of R^(c4) and R^(d4), R^(g4) and R^(h4)and/or R^(j4) and R^(k4) are linked together to form, together with thenitrogen atom to which they are attached, a 3-to 6-membered ring, whichring optionally contains one further heteroatom and which ringoptionally is substituted by one or more groups independently selectedG^(3b); each G^(3a) and G^(3b) independently represents halo, R^(a5),—CN, —N(R^(b5))R^(c5), —OR^(d5), —SR^(e5) or ═O; each R^(a5)independently represents C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl eachoptionally substituted by one or more groups independently selected fromG⁴; each R^(b5), R^(c5), R^(d5) and R^(e5) independently represents H,or C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl each optionally substitutedby one or more groups independently selected from G⁴; or each R^(b5) andR^(c5) are linked together to form, together with the nitrogen atom towhich they are attached, a 3- to 6-membered ring, which ring optionallycontains one further heteroatom and which ring optionally is substitutedby one or more groups independently selected from G⁴; each G⁴independently represents halo, R^(a6), —CN, —N(R^(b6))R^(c6), —OR^(d6)or ═O; each R^(a6) independently represents C₁₋₆ alkyl, C₂₋₆ alkenyl orC₂₋₆ alkynyl each optionally substituted by one or more fluoro; eachR^(b6), R^(c6) and R^(d6) independently represents H, or C₁₋₆ alkyl,C₂₋₆ alkenyl or C₂₋₆ alkynyl each optionally substituted by one or morefluoro; and each p and q independently represents 1 or 2, with theprovisos that the compound of formula I does not represent:3-nitro-2-(pyridin-2-ylsulfonyl)pyridine,2-((3-nitropyridin-2-yl)sulfonyl)pyrimidine, orN-(6-chloro-2-((5-chloro-3-nitropyridin-2-yl)sulfonyl)pyridin-3-yl)acetamide.2. A compound as claimed in claim 1, wherein X is unsubstituted orsubstituted with one or two Y groups.
 3. A compound as claimed in claim1, wherein each Y independently represents halo, R^(a3),—N(R^(j3))R^(k3) or —OR^(l3).
 4. A compound as claimed in claim 1,wherein: each R^(a3) independently represents C₁₋₆ alkyl optionallysubstituted by one or more fluoro; and/or each R^(j3), R^(k3) and R^(l3)independently represents H or C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyleach optionally substituted by one or more fluoro.
 5. A compound asclaimed in claim 1, wherein: X is unsubstituted or substituted with oneY; and/or Y represents halo or C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyleach optionally substituted by one or more fluoro.
 6. A compound asclaimed in claim 1, wherein the compound of formula I is a compound offormula Ia

wherein: each of Z¹ to Z⁵ represents CR⁴ to CR⁸, respectively, with theexception that one or two of Z¹ to Z⁵ instead represents a heteroatom,which where possible may be substituted with R⁹, and optionally one ofZ¹ to Z⁵ may instead represent a direct bond; and each of R⁴ to R⁹represents H or Y.
 7. A compound as claimed in claim 6, wherein each ofR⁴, R⁵, R⁷, R⁸ and R⁹ (where present) represents H and R⁶ (wherepresent) represents H or Y, wherein Y represents methyl optionallysubstituted by one or more fluoro.
 8. A compound as claimed in claim 1,wherein R¹, R² and R³ each independently represents H, halo, R^(a1),—N(R^(i1))R^(k1) or —OR^(l1).
 9. A compound as claimed in claim 1,wherein: R¹, R² and R³ each independently represent H, halo, R^(a1),—N(R^(j1))R^(k1), —OR^(l1) or —SR^(m1); and/or each of R^(a1), R^(j1),R^(k1), R^(l1) and R^(m1) independently represents C₁₋₆ alkyl, C₂₋₆alkenyl or C₂₋₆ alkynyl each optionally substituted by one or morefluoro.
 10. A compound as claimed in claim 1, wherein R¹, R² and R³ eachindependently represent H, halo, —N(R^(i1))R^(k1) or —OR^(l1).
 11. Acompound as claimed in claim 1, wherein: R² and R³ each represent H; R¹represents H, halo, —N(R^(j1))R^(k1) or —OR^(l1); and each R^(j1),R^(k1) and R^(l1) represents C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyleach optionally substituted by one or more fluoro.
 12. A compound asclaimed in claim 1, wherein: R² and R³ each represent H; R¹ representshalo, —N(R^(i1))R^(k1) or —OR^(l1); and each R^(j1), R^(k1) and R^(l1)represents methyl optionally substituted by one or more fluoro.
 13. Amethod of treating cancer comprising administering to a patient in needthereof a therapeutically effective amount of a compound as defined inclaim 1 but without the provisos, wherein the cancer is selected fromthe group consisting of soft tissue cancers, lung cancers,gastrointestinal cancers, breast cancer, genitourinary tract cancers,liver cancers, bone cancers, cancers of the head and/or nervous system,gynecological cancers, hematologic cancers, skin cancers,neurofibromatosis and adrenal gland cancers.
 14. The method of claim 13,wherein the cancer is selected from the group consisting of head andneck cancer, glioblastoma, pharyngeal squamous cell carcinoma,colorectal carcinoma, epidermoid (skin) carcinoma, pancreatic ductalcarcinoma, metastatic mammary adenocarcinoma, lung carcinoma, leukemia,non-small cell lung cancer, colon cancer, melanoma, ovarian cancer,renal cancer, and prostate cancer.
 15. A pharmaceutical compositioncomprising a compound as defined in claim 1 but without the provisos,and optionally one or more pharmaceutically acceptable adjuvant, diluentand/or carrier.
 16. A combination product comprising: (A) a compound asdefined in claim 1, but without the provisos; and (B) one or more othertherapeutic agent that is useful in the treatment of cancer, whereineach of components (A) and (B) is formulated in admixture, optionallywith one or more a pharmaceutically-acceptable adjuvant, diluent orcarrier.
 17. A kit-of-parts comprising: (a) a pharmaceutical compositionas defined in claim 15; and (b)one or more other therapeutic agent thatis useful in the treatment of cancer, optionally in admixture with oneor more pharmaceutically-acceptable adjuvant, diluent or carrier, whichcomponents (a) and (b) are each provided in a form that is suitable foradministration in conjunction with the other.
 18. A process for thepreparation of a compound as defined in claim 1, including the provisos,which process comprises: (i) where n represents 2, reaction of acompound of formula IIA

wherein R¹, R² and R³ are as defined in claim 1 and LG¹ represents asuitable leaving group, with a compound of formula IIIA

wherein X is as defined in claim 1 and M represents an alkali metal ion,in the presence of a suitable acid and in the presence of a suitablesolvent, and optionally in the presence of a suitable phase transfercatalyst; (ii) where n represents 2, reaction of a compound of formulaIIB

wherein R¹, R² and R³ are as defined in claim 1 and M represents analkali metal ion, with a compound of formula IIIB

wherein X is as defined in claim 1 and LG² represents a suitable leavinggroup, in the presence of a suitable acid and in the presence of asuitable solvent, and optionally in the presence of a suitable phasetransfer catalyst; (iii) where n represents 2, reaction of a compound offormula IIA with a compound of formula IIIA, in the presence of asuitable metal halide and in the presence of a suitable solvent; (iv)where n represents 2, reaction of a compound of formula IIB with acompound of formula IIIB, in the presence of a suitable metal halide andin the presence of a suitable solvent; (v) reaction of a compound offormula IV

wherein R¹ to R³ and X are as defined in claim 1, with a suitableoxidising agent in the presence of a suitable solvent, and optionally inthe presence of water; (vi) where n represents 2, reaction of a compoundof formula V

wherein R¹, R² and R³ are as defined in claim 1 and LG³ represents asuitable leaving group with a compound of formula VI

wherein X is as defined in claim 1, in the presence of a suitable Lewisacid and in the presence of a suitable solvent; (vii) where n represents2, reaction of a compound of formula V with a compound of formula VI, inthe presence of a suitable catalyst and a suitable base, and in thepresence of a suitable solvent; (viii) where n represents 2, reaction ofa compound of formula V with a compound of formula VII

wherein X is as defined in claim 1 and LG⁴ represents a suitable leavinggroup, in the presence of a suitable catalyst and in the presence of asuitable solvent; or (ix) where n represents 2, reaction of a compoundof formula IIB with (a) a compound of formula VI having at least one Ygroup, or (b) a compound of formula VI having a group that may beconverted to a Y group, wherein the Y group or group that may beconverted to a Y group is present in the alpha position relative to theessential H substituent and represents a suitable directing group, inthe presence of a suitable catalyst and/or oxidant, and in the presenceof a suitable solvent, which step may further comprise conversion of thegroup that may be converted to a Y group to the required Y group.